Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text (PDF, 148K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hall, R. A. Articles by Lefkowitz, R. J. Search for Related Content PubMed PubMed Citation Articles by Hall, R. A. Articles by Lefkowitz, R. J. Social Bookmarking                            What's this?

© The Rockefeller University Press, 0021-9525/1999//927 $5.00
The Journal of Cell Biology, Volume 145, Number 5, , 1999 927-932

Heptahelical Receptor Signaling: Beyond the G Protein Paradigm

Howard Hughes Medical Institute, Department of Medicine and Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710

Abbreviations used in this paper: GAP, GTPase-activating protein; GRK, G protein–coupled receptor kinase; mGluR, metabotropic glutamate receptor; NHERF, Na⁺/H⁺ exchanger regulatory factor.

Address correspondence to Robert J. Lefkowitz, Howard Hughes Medical Institute, Box 3821, Duke University Medical Center, Durham, NC 27710. Tel.: (919) 684-2974. Fax: (919) 684-8875. E-mail: lefko001{at}mc.duke.edu

HEPTAHELICAL receptors, so called because of their conserved structure featuring seven -helical transmembrane spans, mediate physiological responses to a remarkably diverse array of stimuli. These include hormones, neurotransmitters, small peptides, proteins, lipids and ions, as well as sensory stimuli such as odorants, pheromones, bitter and sweet tastants, and photons. This superfamily of receptors contains >1,000 members, making it the largest class of cell surface molecules in the mammalian genome. Moreover, it was found recently that heptahelical receptors account for >5% of the total genes in the Caenorhabditus elegans genome (Bargmann, 1998), testifying to the importance of this family and demonstrating that the structure of these receptors has been highly conserved throughout evolution. For many years, this family of receptors has been referred to as G protein– coupled, a term based on the well documented paradigm that such receptors interact with and signal through heterotrimeric G proteins. Simply stated, this repeatedly validated paradigm is that when heptahelical receptors are stimulated with ligand, their intracellular regions undergo conformational changes, allowing the receptors to interact with G proteins. This association in turn causes conformational changes in the G proteins that facilitate GDP release and GTP binding, leading to dissociation of G and G_β subunits. The activated G protein subunits then bind to and regulate various intracellular effectors.

During the past few years, however, several reports have appeared in the literature describing various physiological consequences of heptahelical receptor stimulation that, surprisingly, do not seem to be mediated by G protein activation. Concurrently, novel techniques for detecting protein–protein interactions such as yeast two-hybrid, phage display, and fusion protein overlays have revealed associations of heptahelical receptors with a variety of intracellular partners other than G proteins. This convergence of unexplained physiology and provocative protein– protein interactions has led increasingly to the realization that the mechanisms of heptahelical receptor signaling are more diverse than previously thought. This mini-review summarizes recent work on the subject of intracellular signaling by heptahelical receptors through means other than classical G protein pathways.

	Arrestins and G Protein–coupled Receptor Kinases

Top Arrestins and G... SH2 Domain–containing... Small GTP-binding Proteins PDZ Domain–containing... Polyproline-binding Proteins Unsolved Heptahelical Receptor... Beyond the G Protein... References

 
Activated heptahelical receptors are phosphorylated by a family of G protein–coupled receptor kinases (GRKs).¹ Following phosphorylation, the receptors bind to another family of proteins called arrestins (Lefkowitz, 1998). The regions of the receptors that arrestins bind to, generally the third intracellular loop and the portion of the carboxyl-terminal tail closest to the membrane, are also primary determinants for G protein interaction. Arrestin binding to receptors thus results in desensitization of G protein–mediated signaling by preventing interaction of receptors with G proteins. An emerging view, however, is that the binding of arrestins to heptahelical receptors also initiates a new set of signaling pathways in addition to blocking those mediated by G protein activation.

It was proposed recently, for example, that β-arrestin can act as an adaptor protein to recruit the tyrosine kinase Src into a signaling complex organized around the β₂-adrenergic receptor (Luttrell et al., 1999). It is well known that stimulation of many heptahelical receptors can lead to the activation of MAP kinases, but the mechanisms involved have been difficult to define. While G protein activation is clearly necessary, activation of tyrosine kinases of the Src family is required in many cases as well (Luttrell et al., 1996). The most recent findings reveal that Src associates in cells with agonist-activated β₂-adrenergic receptors, as assessed by immunofluorescence and coimmunoprecipitation. The recruitment of cellular Src to β₂-adrenergic receptors is potentiated by overexpression of β-arrestin, and in vitro pull-down studies reveal a direct high-affinity association between Src and β-arrestin. β-Arrestin–mediated association of Src with β₂-adrenergic receptors is a key step in mitogenic signaling by these receptors, since inhibition of the binding of β-arrestin to either the β₂-adrenergic receptor or Src attenuates β₂-adrenergic activation of MAP kinase. These results indicate that the association of arrestins with heptahelical receptors does not simply uncouple receptors from G protein pathways, but rather induces a switch in receptor signaling from classical second messenger–generating G protein–mediated pathways to other pathways such as those involving Src and leading to the activation of MAP kinase. Moreover, arrestins have also been found to interact with a number of cellular proteins involved in endocytosis such as clathrin heavy chain (Goodman et al., 1996), the clathrin adaptor AP-2 (Laporte et al., 1999), and NSF (N-ethylmaleimide sensitive fusion protein) (McDonald et al., 1999). These interactions represent potential mechanisms by which heptahelical receptors might directly regulate the cellular endocytic machinery. Thus, arrestins may well represent multifunctional adaptor proteins that mediate a number of aspects of heptahelical receptor signaling.

GRKs may also be signaling intermediates for heptahelical receptors rather than just proteins involved in receptor desensitization. Recently, it was found that GRK2 can associate with and phosphorylate tubulin (Carman et al., 1998; Haga et al., 1998; Pitcher et al., 1998). GRKs have also been shown to associate with actin (Freeman et al., 1998) and a novel ARF GTPase-activating protein (ARF GAP) called GIT1 (Premont et al., 1998). These findings illustrate at least two ways in which the recruitment of GRKs to activated heptahelical receptors may lead directly to cytoskeletal regulation or to modulation of other intracellular processes: (a) allosteric activation of GRKs by ligand-occupied receptors (Palczewski et al., 1991; Chen et al., 1993; Premont et al., 1994) may catalyze the phosphorylation of key nonreceptor substrates such as tubulin; and (b) GRKs may act as noncatalytic adaptors to recruit key signaling intermediates (e.g., an ARF GAP) into complex with the receptors at the plasma membrane.

	SH2 Domain–containing Signaling Proteins

Top Arrestins and G... SH2 Domain–containing... Small GTP-binding Proteins PDZ Domain–containing... Polyproline-binding Proteins Unsolved Heptahelical Receptor... Beyond the G Protein... References

 
Several subtypes of heptahelical receptors have been proposed to organize SH2 domain–based signaling complexes in a manner analogous to that seen for receptor tyrosine kinases. The heptahelical angiotensin AT₁ receptor, for example, activates the Jak2 tyrosine kinase following stimulation with angiotensin II (Marrero et al., 1995). The mechanism underlying this effect involves Src-mediated tyrosine phosphorylation of the AT₁ receptor itself (Venema et al., 1998). It is interesting to speculate that this phosphorylation might result from β-arrestin–mediated recruitment of Src to the receptor, but at present this idea has not been tested. When Tyr319 on the AT₁ receptor carboxyl-terminal tail is phosphorylated, Jak2 coimmunoprecipitates with the AT₁ receptor in an agonist-dependent fashion; mutation of Tyr319 to Phe blocks coimmunoprecipitation of Jak2 with AT₁ receptors and also attenuates Jak2 activation mediated by angiotensin II stimulation (Ali et al., 1997). Originally, it was thought that Jak2 interaction with the AT₁ receptor was direct. Jak2 does not have an SH2 domain, however, so it was not clear how it could bind to the AT₁ receptor tail in a phosphotyrosine-dependent manner. Subsequent studies revealed that the Jak2/AT₁ receptor tail interaction can be blocked by antibodies to the SHP family of SH2 domain– containing tyrosine phosphatases (Marrero et al., 1998), indicating that SHP proteins probably act as adaptors to facilitate the association of Jak2 with the AT₁ receptor. It has also been shown that another SH2 domain–containing protein, phospholipase C1, can be coimmunoprecipitated with the tyrosine-phosphorylated AT₁ receptor (Venema et al., 1998), although the significance of this interaction for downstream signaling by the receptor has not yet been clarified.

The β₂-adrenergic receptor is phosphorylated on tyrosine by the insulin receptor tyrosine kinase (Hadcock et al., 1992; Karoor et al., 1995; Valiquette et al., 1995; Baltensperger et al., 1996). Several tyrosines in the β₂-adrenergic receptor have been shown to be phosphorylated, and it has also been reported that the SH2 domain–containing adaptor protein Grb2 can associate with β₂-adrenergic receptors following phosphorylation of Tyr350/354 on the receptor (Karoor et al., 1998). It is not yet known, however, if this association mediates any downstream signaling by the β₂-adrenergic receptor. Nonetheless, given these provocative findings with the AT₁ and β₂-adrenergic receptors, a significant point of future interest will be to see if other heptahelical receptors may be tyrosine-phosphorylated and thus capable of hosting SH2 or PTB domain–based signaling complexes.

	Small GTP-binding Proteins

Top Arrestins and G... SH2 Domain–containing... Small GTP-binding Proteins PDZ Domain–containing... Polyproline-binding Proteins Unsolved Heptahelical Receptor... Beyond the G Protein... References

 
Heptahelical receptor–mediated regulation of small GTP-binding proteins, such as Ras, Rab, Rho, and ARF, has been studied for years but has typically been viewed as a downstream consequence of heterotrimeric G protein activation (Buhl et al., 1995; Kozasa et al., 1998). Recently, however, it has been shown that activation of phospholipase D by certain heptahelical receptors, including M₃ muscarinic acetylcholine receptors and H₁ histamine receptors, is not blocked by inhibitors of heterotrimeric G protein pathways, such as pertussis toxin or phospholipase C inhibitors, but is sensitive to the ARF inhibitor brefeldin A and the Rho inhibitor C3 botulinum toxin (Mitchell et al., 1998). ARF and Rho can also be immunoprecipitated in an agonist-dependent fashion in association with M₃ muscarinic receptors and AT₁ angiotensin receptors. The receptors capable of binding ARF and Rho exhibit a conserved motif (N-P-x-x-Y) in their seventh transmembrane span. Mutation of this motif prevents association of the receptors with ARF and Rho and also alters receptor signaling to phospholipase D. While it is not clear at present if the association of ARF and Rho with the heptahelical receptors is direct, it is clear that these small GTP-binding proteins can form a complex with some heptahelical receptors and that formation of this complex can mediate signaling of these receptors to phospholipase D.

	PDZ Domain–containing Proteins

Top Arrestins and G... SH2 Domain–containing... Small GTP-binding Proteins PDZ Domain–containing... Polyproline-binding Proteins Unsolved Heptahelical Receptor... Beyond the G Protein... References

 
The heptahelical receptor-binding proteins discussed so far (heterotrimeric G proteins, arrestins, GRKs, SH2 proteins, and small GTP-binding proteins) all bind to either the receptor third intracellular loop or the portion of the receptor tail nearest the plasma membrane. Many heptahelical receptors, however, have quite long intracellular carboxyl-terminal tails, suggesting that the distal portions of some receptor tails may also be capable of mediating association with various intracellular signaling proteins. Moreover, the carboxyl-terminal tails of some heptahelical receptors terminate in variants of the T/S-x-V motif required for binding to PDZ domain–containing proteins such as PSD-95 (Kornau et al., 1995).

One example of a heptahelical receptor with a long intracellular tail is the β₂-adrenergic receptor. Overlay studies demonstrated that the tail of this receptor binds with very high affinity to a single protein in tissue extracts; subsequent purification and sequencing revealed this binding partner to be a PDZ domain–containing protein, the Na⁺/ H⁺ exchanger regulatory factor (NHERF) (Hall et al., 1998a). NHERF binds not only to the β₂-adrenergic receptor tail in vitro, but also to the full-length β₂-adrenergic receptor in cells in an agonist-dependent fashion as assessed by immunofluorescence studies.

β₂-Adrenergic regulation of renal Na⁺/H⁺ exchange has long been known to be opposite of what would be expected from a G_s-coupled receptor. Activation of G_s-coupled receptors such as parathyroid hormone receptors increases cellular cyclic AMP, which in a PKA-dependent fashion facilitates the association of NHERF with renal Na⁺/H⁺ exchangers and thus leads to inhibition of Na⁺/H⁺ exchange (Weinman and Shenolikar, 1993). Activation of β₂-adrenergic receptors also increases cellular cyclic AMP, yet paradoxically leads to stimulation of renal Na⁺/H⁺ exchange (Bello-Reuss, 1980; Weinman et al., 1982). A point mutant of the β₂-adrenergic receptor with the final residue of the receptor changed from leucine to alanine, which cannot bind NHERF but which exhibits normal G protein coupling, inhibits the activity of the renal Na⁺/H⁺ exchanger in cells rather than stimulating it like the wild-type receptor (Hall et al., 1998a). These findings suggest that the ability of the β₂-adrenergic receptor to bind NHERF is critical for β₂-adrenergic regulation of renal Na⁺/H⁺ exchange in vivo.

Rhodopsin is another heptahelical receptor that has been found to associate with a PDZ domain–containing protein in a functionally relevant manner. Rhodopsin binds to InaD (Chevesich et al., 1997; Xu et al., 1998), a multi-PDZ domain scaffolding protein that also associates with a number of signaling intermediates involved in rhodopsin-initiated pathways, such as phospholipase Cβ, protein kinase C, and the TRP ion channel (Huber et al., 1996; Shieh and Zhu, 1996; Chevesich et al., 1997; Tsunoda et al., 1997; Xu et al., 1998). Mutations in InaD profoundly distort photon-induced rhodopsin signaling (Scott and Zuker, 1998). The physical association of rhodopsin and InaD has been demonstrated by coimmunoprecipitation and by in vitro fusion protein pull-down experiments (Chevesich et al., 1997; Xu et al., 1998), but it is not known at present if the association of InaD and rhodopsin in cells occurs constitutively or if instead it is promoted by photoactivation of rhodopsin. In any case, it seems that rhodopsin can facilitate the assembly of intracellular protein complexes involved in phototransduction via its interaction with InaD.

The interactions of PDZ domains with the carboxyl termini of their target proteins are quite specific (Songyang et al., 1997). As demonstrated by the β₂-adrenergic receptor point mutant, a change of a single amino acid can be enough to completely disrupt an otherwise high-affinity association. Only a small number of heptahelical receptors terminate in the carboxyl-terminal motif (S/T-x-L) required for high-affinity NHERF binding (Hall et al., 1998b). However, since the >50 known PDZ domain–containing proteins recognize diverse target motifs, it is probable that some of these proteins associate with specific heptahelical receptors in a functionally relevant manner. Signaling through PDZ domain–mediated associations may therefore be a feature common to many heptahelical receptors.

	Polyproline-binding Proteins

Top Arrestins and G... SH2 Domain–containing... Small GTP-binding Proteins PDZ Domain–containing... Polyproline-binding Proteins Unsolved Heptahelical Receptor... Beyond the G Protein... References

 
Several heptahelical receptors exhibit polyproline regions on either their third intracellular loops or carboxyl-terminal tails. Polyproline regions are known to mediate binding to a variety of conserved protein domains such as SH3 domains, WW domains, and EVH domains (Pawson and Scott, 1997). Recently, several subtypes of heptahelical metabotropic glutamate receptor (mGluR) were shown to bind members of the Homer family of EVH domain–containing proteins through a polyproline region found in the mGluR tail region (Brakeman et al., 1997; Tu et al., 1998; Xiao et al., 1998). This binding has been shown in yeast two-hybrid studies, fusion protein pull-downs, and coimmunoprecipitation studies. Some members of the Homer family can dimerize, and are thus capable of linking mGluRs to other proteins with appropriate polyproline motifs. For example, Homer proteins can facilitate a functional interaction between mGluRs and endoplasmic reticulum–based inositol trisphosphate (IP3) receptors, which control intracellular calcium release. When the mGluR/ Homer association is blocked, the ability of mGluRs to mobilize intracellular calcium is attenuated (Tu et al., 1998). These findings suggest that Homer is a key intermediate in mGluR regulation of intracellular calcium levels, and thus shed light on the puzzling observation made shortly after the cloning of the mGluRs that alternative splicing of the mGluR1 carboxyl-terminal tail results in profound differences in the ability of this receptor to mobilize intracellular calcium (Pin et al., 1992; Joly et al., 1995).

Another heptahelical receptor that can bind signaling proteins through a polyproline region is the dopamine D4 receptor, which contains a stretch of prolines in its third intracellular loop. This polyproline region in the D4 receptor can mediate in vitro binding to a number of SH3 domain–containing proteins, including Grb2 and Nck, as assessed by yeast two-hybrid and protein pull-down assays (Oldenhof et al., 1998). It is not clear at present, however, which polyproline-binding proteins are the relevant cellular partners for D4 receptors or for other polyproline-containing heptahelical receptors such as β₁-adrenergic receptors and M4 muscarinic receptors. Further work in this area should reveal which polyproline-binding proteins couple to which receptors in cells, as well as what the consequences of these interactions are for receptor signaling.

	Unsolved Heptahelical Receptor Mysteries

Top Arrestins and G... SH2 Domain–containing... Small GTP-binding Proteins PDZ Domain–containing... Polyproline-binding Proteins Unsolved Heptahelical Receptor... Beyond the G Protein... References

 
Several heptahelical receptor binding partners have been identified for which no clear roles in downstream signaling have yet been demonstrated. Examples include the interaction of Grb2 with the β₂-adrenergic receptor and dopamine D4 receptor, as described above, as well as the interaction of the β₂-adrenergic receptor and some -adrenergic receptor subtypes with the subunit of the eukaryotic initiation factor 2B (Klein et al., 1997), and the interaction of the bradykinin B2 receptor with endothelial nitric oxide synthase (Ju et al., 1998). The recent proliferation of techniques for detecting protein–protein interactions is likely to lead to an increase in the number of known binding partners for various heptahelical receptors. Each of these interactions will represent a new potential mechanism of heptahelical receptor signaling, although the true physiological significance of each interaction may not be immediately obvious.

While such lines of research are describing novel mechanisms by which heptahelical receptors may generate intracellular signals, other lines of research are describing physiological effects mediated by heptahelical receptors for which the molecular mechanisms are unknown. Genetic studies in invertebrates, in particular, have yielded a number of examples of heptahelical receptors mediating physiological actions through pathways that are apparently independent of G proteins. For instance, the cyclic AMP receptors of the slime mold Dictyostelium discoideum are heptahelical receptors that induce chemotaxis of undifferentiated Dictyostelium cells into an aggregated fruiting body. These chemotactic effects of Dictyostelium cyclic AMP receptor stimulation are known to be mediated through G protein activation (Devreotes, 1994). However, aggregated Dictyostelium cells undergo a number of cyclic AMP receptor–mediated transcriptional changes that are independent of G protein activation, since cells with G protein subunits deleted still exhibit these changes following stimulation by cyclic AMP (Milne et al., 1995; Schnitzler et al., 1995; Maeda et al., 1996; Jin et al., 1998). The mechanisms by which this class of heptahelical receptors might mediate G protein–independent effects, however, are completely unknown.

More genetic evidence for signaling by heptahelical receptors through means other than traditional G protein pathways comes from the study of a family of receptors known as frizzled. In many species, ranging from C. elegans to Drosophila to mammals, tissue polarity during development is regulated by the Wnt family of secreted proteins, which exert their effects on developing cells by binding to members of the frizzled family (Bhanot et al., 1996; Yang-Snyder et al., 1996; He et al., 1997). Activation of some frizzled family heptahelical receptors results in increases in cellular calcium that can be inhibited by modulators of G protein function such as pertussis toxin and GDP-β-S (Slusarski et al., 1997). Thus, it seems that frizzled receptors can couple to G proteins. However, genetic studies have identified a number of signaling intermediates downstream of frizzled, such as dishevelled, glycogen synthase kinase-3, β-catenin, and the product of the adenomatous polyopsis coli (APC) gene (Dale, 1998), and none of these proteins resemble known components of classical G protein signaling pathways.

Dishevelled is the most proximal frizzled signaling intermediate identified. It is not known if the interaction between frizzled and dishevelled is direct, but it is interesting to note that dishevelled contains a PDZ domain and many frizzled family members possess carboxyl-terminal motifs appropriate for PDZ domain association. Therefore, it is possible that members of the frizzled family may signal through direct coupling to PDZ domain–containing proteins like dishevelled in a manner analogous to the PDZ domain–mediated interaction of the β₂-adrenergic receptor with NHERF. Some components of frizzled signaling pathways have been identified as oncogenes in mammalian tissues (Kinzler and Vogelstein, 1996), emphasizing the importance of understanding frizzled signaling.

Another genetically identified heptahelical receptor that signals via unknown mechanisms is smoothened. This receptor is a relative of the frizzled family of receptors, and is a key mediator of hedgehog signaling (Alcedo et al., 1996; van den Heuvel and Ingham, 1996). Hedgehog, a soluble protein first identified as a regulator of patterning during Drosophila development, binds to a cell surface receptor known as patched (Chen and Struhl, 1996; Stone et al., 1996), which leads to regulation of the activity of smoothened to exert control over cell proliferation and differentiation. Since smoothened is a heptahelical receptor, much attention has been focused on the possibility that it might couple to heterotrimeric G proteins, but at present there is no conclusive evidence for such coupling. Indeed, genetic studies have identified several key proteins, such as the serine/threonine kinase fused and the putative transcriptional factor cubitus interruptus, as intermediates in the smoothened signaling pathway; none of these proteins resemble known components of G protein signaling pathways (Ingham, 1998). Activating mutations in the mammalian homologue of smoothened have been identified recently as underlying causes of sporadic basal-cell carcinoma (Xie et al., 1998), revealing that smoothened, like frizzled, may be involved in carcinogenesis. The intracellular signaling mechanisms used by both frizzled and smoothened are thus of interest not just as novel examples of heptahelical receptor signaling, but also as potential points of clinical intervention in the treatment of some cancers.

	Beyond the G Protein Paradigm

Top Arrestins and G... SH2 Domain–containing... Small GTP-binding Proteins PDZ Domain–containing... Polyproline-binding Proteins Unsolved Heptahelical Receptor... Beyond the G Protein... References

 
Over the past several years, evidence has emerged that heptahelical receptors can signal through associations with intracellular partners other than G proteins. In some cases, these partners are known receptor-interacting proteins, such as arrestins and GRKs, which were thought previously to be involved only in receptor desensitization. In other cases, they are novel partners such as NHERF or Homer, which were not known previously to interact with heptahelical receptors. For heptahelical receptors that seem to mediate physiological effects via unknown G protein–independent pathways, such as frizzled and smoothened, it might be useful to consider analogies with other heptahelical receptors for which the early steps of various G protein–independent signaling mechanisms have been elucidated. Some of these mechanisms are likely to be quite general: for example, arrestins and GRKs can bind to many heptahelical receptors, and arrestin- and GRK-mediated formation of signaling complexes may therefore be a feature common to many heptahelical receptors. Other mechanisms, such as the activation of small GTP-binding proteins or the formation of SH2-based signaling complexes organized around tyrosine-phosphorylated residues, may be relevant to a small number of heptahelical receptors but not to the majority. Still other mechanisms are likely to be highly receptor-specific: the binding of NHERF to the β₂-adrenergic receptor and the binding of Homer to metabotropic glutamate receptors, for example, depend on the presence of precise motifs that are likely to be found in few other heptahelical receptors, although other receptors are likely to contain slightly modified motifs that mediate binding to other specific PDZ or polyproline-binding domains.

There are >1,000 heptahelical receptors but only 20 different heterotrimeric G proteins. Such an arrangement would seem to place limitations on the specificity of heptahelical receptor signal transduction, if G proteins were the only mediators of heptahelical receptor–initiated signaling. However, it now seems likely that each heptahelical receptor may activate its own relatively specific set of intracellular signaling pathways, including both G protein– dependent and G protein–independent mechanisms (Fig. 1). The net physiological effect of stimulation of a particular heptahelical receptor will thus reflect the sum of the various intracellular pathways it can activate, with some of the pathways being quite general, others being fairly specific, and some being unique to the individual receptor.

View larger version (33K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Schematic diagram of heptahelical receptor signaling. (A) The G protein paradigm. Following agonist binding, heptahelical receptors activate heterotrimeric G proteins (G), which then regulate the activity of specific cellular effectors. (B) Beyond the G protein paradigm. Following agonist binding, heptahelical receptors can associate with members of diverse families of intracellular proteins, including heterotrimeric G proteins (G), polyproline-binding proteins such as those containing SH3 domains (SH3), arrestins (Arr), G protein–coupled receptor kinases (GRK), small GTP-binding proteins (g), SH2 domain–containing proteins (SH2) and PDZ domain–containing proteins (PDZ). These interactions allow heptahelical receptors to initiate multiple intracellular signaling pathways, with each subtype of receptor likely coupled to a relatively unique set of effectors.

	Acknowledgments

 
The authors would like to thank Audrey Claing, Stéphane Laporte, and Lou Luttrell for helpful comments on this manuscript.

Submitted: 9 April 1999

Revised: 26 April 1999

R.J. Lefkowitz is an investigator of the Howard Hughes Medical Institute.

	References

Top Arrestins and G... SH2 Domain–containing... Small GTP-binding Proteins PDZ Domain–containing... Polyproline-binding Proteins Unsolved Heptahelical Receptor... Beyond the G Protein... References

 

Alcedo J, Ayzenzon M, Von Ohlen T, Noll M & Hooper JE. The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehogsignal, Cell, 1996, 86, 221–232.[Medline]

Ali MS, Sayeski PP, Dirksen LB, Hayzer DJ, Marrero MB & Bernstein KE. Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT₁receptor, J Biol Chem, 1997, 272, 23382–23388.[Abstract/Free Full Text]

Baltensperger K, Karoor V, Paul H, Ruoho A, Czech MP & Malbon CC. The β-adrenergic receptor is a substrate for the insulin receptor tyrosine kinase, J Biol Chem, 1996, 271, 1061–1064.[Abstract/Free Full Text]

Bargmann CI. Neurobiology of the Caenorhabditis elegansgenome, Science, 1998, 282, 2028–2033.[Abstract/Free Full Text]

Bello-Reuss E. Effect of catecholamines on fluid reabsorption by the isolated proximal convoluted tubule, Am J Physiol, 1980, 238, F347–F352.[Medline]

Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, Andrew D, Nathans J & Nusse R. A new member of the frizzled family from Drosophilafunctions as a Wingless receptor, Nature, 1996, 382, 225–230.[Medline]

Brakeman PR, Lanahan AA, O'Brien R, Roche K, Barnes CA, Huganir RL & Worley PF. Homer: a protein that selectively binds metabotropic glutamate receptors, Nature, 1997, 386, 284–288.[Medline]

Buhl AM, Johnson NL, Dhanasekaran N & Johnson GL. G12 and G13 stimulate Rho-dependent stress fiber formation and focal adhesion assembly, J Biol Chem, 1995, 270, 24631–24634.[Abstract/Free Full Text]

Carman CV, Som T, Kim CM & Benovic JL. Binding and phosphorylation of tubulin by G protein-coupled receptor kinases, J Biol Chem, 1998, 273, 20308–20316.[Abstract/Free Full Text]

Chen C-Y, Dion SB, Kim CM & Benovic JL. β-adrenergic receptor kinase: agonist-dependent receptor binding promotes kinase activation, J Biol Chem, 1993, 268, 7825–7831.[Abstract/Free Full Text]

Chen Y & Struhl G. Dual roles for patched in sequestering and transducing Hedgehog. , Cell, 1996, 87, 553–563.[Medline]

Chevesich J, Kreuz AJ & Montell C. Requirement for the PDZ domain protein, InaD, for localization of the TRP store-operated channel to a signaling complex, Neuron, 1997, 18, 95–105.[Medline]

Dale TC. Signal transduction by the Wnt family of ligands, Biochem J, 1998, 329, 209–223.[Medline]

Devreotes PN. G protein-linked signaling pathways control the developmental program of Dictyostelium. , Neuron, 1994, 12, 235–241.[Medline]

Freeman JL, De La Cruz EM, Pollard TD, Lefkowitz RJ & Pitcher JA. Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin, J Biol Chem, 1998, 273, 20653–20657.[Abstract/Free Full Text]

Goodman OB Jr, Krupnick JG, Gurevich VV, Benovic JL & Keen JH. β-arrestin acts as a clathrin adaptor in endocytosis of the β₂-adrenergic receptor, Nature, 1996, 383, 447–450.[Medline]

Hadcock JR, Port JD, Gelman MS & Malbon CC. Cross-talk between tyrosine kinase and G-protein-coupled receptors. Phosphorylation of β₂-adrenergic receptors in response to insulin, J Biol Chem, 1992, 267, 26017–26022.[Abstract/Free Full Text]

Haga K, Ogawa H, Haga T & Murofushi H. GTP-binding-protein-coupled receptor kinase 2 (GRK2) binds and phosphorylates tubulin, Eur J Biochem, 1998, 255, 363–368.[Medline]

Hall RA, Premont RT, Chow C-W, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ et al.. The β₂-adrenergic receptor interacts with the Na⁺/H⁺-exchanger regulatory factor to control Na⁺/H⁺exchange, Nature, 1998a, 392, 626–630.[Medline]

Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ & Lefkowitz RJ. A C-terminal motif found in the β₂-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na⁺/H⁺exchanger regulatory factor family of PDZ proteins, Proc Natl Acad Sci USA, 1998b, 95, 8496–8501.[Abstract/Free Full Text]

He X, Saint-Jeannet JP, Wang Y, Nathans J, Dawid I & Varmus H. A member of the Frizzledprotein family mediating axis induction by Wnt-5A, Science, 1997, 275, 1652–1654.[Abstract/Free Full Text]

Huber A, Sander P, Gobert A, Bahner M, Hermann R & Paulsen R. The transient receptor potential protein (TRP), a putative store-operated Ca²⁺channel essential for phosphoinositide-mediated photoreception, forms a signaling complex with NorpA, InaC and InaD, EMBO (Eur Mol Biol Organ) J, 1996, 15, 7036–7045.[Medline]

Ingham PW. Transducing Hedgehog: the story so far, EMBO (Eur Mol Biol Organ) J, 1998, 17, 3505–3511.[Medline]

Jin T, Soede RDM, Liu J, Kimmel AR, Devreotes PN & Schaap P. Temperature-sensitive Gβ mutants discriminate between G protein-dependent and -independent signaling mediated by serpentine receptors, EMBO (Eur Mol Biol Organ) J, 1998, 17, 5076–5084.[Medline]

Joly C, Gomeza J, Brabet I, Curry K, Bockaert J & Pin J-P. Molecular, functional and pharmacological characterization of the metabotropic glutamate receptor type 5 splice variants: comparison with mGluR1, J Neurosci, 1995, 15, 3970–3981.[Abstract]

Ju H, Venema VJ, Marrero MB & Venema RC. Inhibitory interactions of the bradykinin B2 receptor with endothelial nitric oxide synthase, J Biol Chem, 1998, 273, 24025–24029.[Abstract/Free Full Text]

Karoor V, Baltensperger K, Paul H, Czech MP & Malbon CC. Phosphorylation of tyrosyl residues 350/354 of the beta-adrenergic receptor is obligatory for counterregulatory effects of insulin, J Biol Chem, 1995, 270, 25305–25308.[Abstract/Free Full Text]

Karoor V, Wang L, Wang H-Y & Malbon CC. Insulin stimulates sequestration of beta-adrenergic receptors and enhanced association of beta-adrenergic receptor with Grb2 via tyrosine 350, J Biol Chem, 1998, 273, 33035–33041.[Abstract/Free Full Text]

Kinzler KW & Vogelstein B. Lessons from hereditary colorectal cancer, Cell, 1996, 87, 159–170.[Medline]

Klein W, Ramirez MT, Kobilka BK & von Zastrow M. A novel interaction between adrenergic receptors and the -subunit of the eukaryotic initiation factor 2B, J Biol Chem, 1997, 272, 19099–19102.[Abstract/Free Full Text]

Kornau H-C, Schenker LT, Kennedy MB & Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95, Science, 1995, 269, 1737–1740.[Abstract/Free Full Text]

Kozasa T, Jiang X, Hart MJ, Sternweis PC, Singer WD, Gilman AG, Bollag G & Sternweis PC. p115 RhoGEF, a GTPase activating protein for G12 and G13, Science, 1998, 280, 2109–2111.[Abstract/Free Full Text]

Laporte S, Oakley RH, Zhang J, Holt JA, Ferguson SSG, Caron MG & Barak LS. The β₂-adrenergic receptor/β-arrestin complex recruits the clathrin adaptor AP-2 during endocytosis, Proc Natl Acad Sci USA, 1999, 96, 3712–3717.[Abstract/Free Full Text]

Lefkowitz RJ. G protein-coupled receptors. III. New roles for receptor kinases and β-arrestins in receptor signaling and desensitization, J Biol Chem, 1998, 273, 18677–18680.[Free Full Text]

Luttrell LM, Hawes BE, van Biesen T, Luttrell DK, Lansing TJ & Lefkowitz RJ. Role of c-Src tyrosine kinase in G protein-coupled receptor- and Gbetagamma subunit-mediated activation of mitogen-activated protein kinases, J Biol Chem, 1996, 271, 19443–19450.[Abstract/Free Full Text]

Luttrell LM, Ferguson SSG, Daaka Y, Miller WE, Maudsley S, Della GJ, Rocca, Lin F-T, Kawakatsu H, Owada K, Luttrell DK et al.. β-arrestin-dependent formation of β₂-adrenergic receptor-Src protein kinase complexes, Science, 1999, 283, 655–661.[Abstract/Free Full Text]

Maeda M, Aubry L, Insall R, Gaskins C, Devreotes PN & Firtel RA. Seven helix chemoattractant receptors transiently stimulate mitogen-activated protein kinase in Dictyostelium.Role of heterotrimeric G proteins, J Biol Chem, 1996, 271, 3351–3354.[Abstract/Free Full Text]

Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P & Bernstein KE. Direct stimulation of Jak/STAT pathway by the angiotensin II AT₁receptor, Nature, 1995, 375, 247–250.[Medline]

Marrero MB, Venema VJ, Ju H, Eaton DC & Venema RC. Regulation of angiotensin II-induced Jak2 tyrosine phosphorylation: roles of SHP-1 and SHP-2, Am J Physiol, 1998, 275, C1216–C1223.[Medline]

McDonald PH, Cote NL, Lin F-T, Premont RT, Pitcher JA & Lefkowitz RJ. Identification of NSF as a β-arrestin1 binding protein; implications for β₂-adrenergic receptor regulation, J Biol Chem, 1999, 274, 10677–10680.[Abstract/Free Full Text]

Milne JL, Wu L, Caterina MJ & Devreotes PN. Seven helix cAMP receptors stimulate Ca2+ entry in the absence of functional G proteins in Dictyostelium. , J Biol Chem, 1995, 270, 5926–5931.[Abstract/Free Full Text]

Mitchell R, McCulloch D, Lutz E, Johnson M, MacKenzie C, Fennell M, Fink G, Zhou W & Sealfon SC. Rhodopsin-family receptors associate with small G proteins to activate phospholipase D, Nature, 1998, 392, 411–414.[Medline]

Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M & Van Tol HH. SH3 binding domains in the dopamine D4 receptor, Biochemistry, 1998, 37, 15726–15736.[Medline]

Palczewski K, Buczylko J, Kaplan MW, Polans AS & Crabb JW. Mechanism of rhodopsin kinase activation, J Biol Chem, 1991, 266, 12949–12955.[Abstract/Free Full Text]

Pawson T & Scott JD. Signaling through scaffold, anchoring, and adaptor proteins, Science, 1997, 278, 2075–2080.[Abstract/Free Full Text]

Pin J-P, Waeber C, Prezeau L, Bockaert J & Heineman SF. Alternative splicing generates metabotropic glutamate receptors inducing different patterns of calcium release in Xenopusoocytes, Proc Natl Acad Sci USA, 1992, 89, 10331–10335.[Abstract/Free Full Text]

Pitcher JA, Hall RA, Daaka Y, Zhang J, Ferguson SS, Hester S, Miller S, Caron MG, Lefkowitz RJ & Barak LS. The G protein-coupled receptor kinase 2 is a microtubule-associated protein kinase that phosphorylates tubulin, J Biol Chem, 1998, 273, 12316–12324.[Abstract/Free Full Text]

Premont RT, Koch WJ, Inglese J & Lefkowitz RJ. Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases, J Biol Chem, 1994, 269, 6832–6841.[Abstract/Free Full Text]

Premont RT, Claing A, Vitale N, Freeman JL, Pitcher JA, Patton WA, Moss J, Vaughan M & Lefkowitz RJ. β₂-adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein, Proc Natl Acad Sci USA, 1998, 95, 14082–14087.[Abstract/Free Full Text]

Schnitzler GR, Briscoe C, Brown JM & Firtel RA. Serpentine cAMP receptors may act through a G-protein-independent pathway to induce postaggregative development in Dictyostelium. , Cell, 1995, 81, 737–745.[Medline]

Scott K & Zuker CS. Assembly of the Drosophilaphototransduction cascade into a signalling complex shapes elementary responses, Nature, 1998, 395, 805–808.[Medline]

Shieh B-H & Zhu M-Y. Regulation of the TRP Ca²⁺ channel by InaD in Drosophilaphotoreceptors, Neuron, 1997, 16, 991–998.[Medline]

Slusarski DC, Corces VG & Moon RT. Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signaling, Nature, 1997, 390, 410–413.[Medline]

Songyang Z, Fanning AS, Fu C, Xu J, Marfatia SM, Chishti AH, Crompton A, Chan AC, Anderson JM & Cantley LC. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains, Science, 1997, 275, 73–77.[Abstract/Free Full Text]

Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, Scott MP, Pennica D, Goddard A, Phillips H et al.. The tumour-suppressor gene patchedencodes a candidate receptor for Sonic hedgehog, Nature, 1996, 384, 129–134.[Medline]

Tsunoda S, Sierralta J, Sun Y, Bodner R, Suzuki E, Becker A, Socolich M & Zuker CS. A multivalent PDZ-domain protein assembles signaling complexes in a G-protein-coupled cascade, Nature, 1997, 388, 243–249.[Medline]

Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ & Worley PF. Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors, Neuron, 1998, 21, 717–726.[Medline]

Valiquette M, Parent S, Loisel TP & Bouvier M. Mutation of tyrosine-141 inhibits insulin-promoted tyrosine phosphorylation and increased responsiveness of the human β₂-adrenergic receptor, EMBO (Eur Mol Biol Organ) J, 1995, 14, 5542–5549.[Medline]

Van den Heuvel M & Ingham PW. Smoothened encodes a receptor-like serpentine protein required for hedgehogsignaling, Nature, 1996, 382, 547–551.[Medline]

Venema RC, Ju H, Venema VJ, Schieffer B, Harp JB, Ling BN, Eaton DC & Marrero MB. Angiotensin II-induced association of phospholipase C1 with the G-protein-coupled AT₁receptor, J Biol Chem, 1998, 273, 7703–7708.[Abstract/Free Full Text]

Weinman EJ & Shenolikar S. Regulation of the renal brush border membrane Na⁺/H⁺exchanger, Annu Rev Physiol, 1993, 55, 289–304.[Medline]

Weinman EJ, Sansom SC, Knight TF & Senekjian HO. Alpha and beta adrenergic agonists stimulate water absorption in the rat proximal tubule, J Memb Biol, 1982, 69, 107–111.[Medline]

Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD, Ruggiero A, Lanahan AA, Wenthold RJ & Worley PF. Homer regulates the association of Group 1 metabotropic glutamate receptors with multivalent complexes of Homer-related, synaptic proteins, Neuron, 1998, 21, 707–716.[Medline]

Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A et al.. Activating Smoothenedmutations in sporadic basal-cell carcinoma, Nature, 1998, 391, 90–92.[Medline]

Xu X-ZS, Choudhury A, Li X & Montell C. Coordination of an array of signaling proteins through homo- and heteromeric interactions between PDZ domains and target proteins, J Cell Biol, 1998, 142, 545–555.[Abstract/Free Full Text]

Yang-Snyder J, Miller JR, Brown LD, Lai CJ & Moon RT. A frizzled homolog functions in a vertebrate Wntsignaling pathway, Curr Biol, 1996, 6, 1302–1306.[Medline]

CiteULike

Complore

Connotea

Del.icio.us

Digg

Facebook

Reddit

Technorati

Twitter

This article has been cited by other articles:

• Ahn, S., Kim, J., Hara, M. R., Ren, X.-R., Lefkowitz, R. J. (2009). {beta}-Arrestin-2 Mediates Anti-apoptotic Signaling through Regulation of BAD Phosphorylation. J. Biol. Chem. 284: 8855-8865 [Abstract] [Full Text]  
• Zhang, L., Zhao, H., Qiu, Y., Loh, H. H., Law, P.-Y. (2009). Src Phosphorylation of {micro}-Receptor Is Responsible for the Receptor Switching from an Inhibitory to a Stimulatory Signal. J. Biol. Chem. 284: 1990-2000 [Abstract] [Full Text]  
• Gong, K., Li, Z., Xu, M., Du, J., Lv, Z., Zhang, Y. (2008). A Novel Protein Kinase A-independent, {beta}-Arrestin-1-dependent Signaling Pathway for p38 Mitogen-activated Protein Kinase Activation by {beta}2-Adrenergic Receptors. J. Biol. Chem. 283: 29028-29036 [Abstract] [Full Text]  
• Lu, R., Alioua, A., Kumar, Y., Kundu, P., Eghbali, M., Weisstaub, N. V., Gingrich, J. A., Stefani, E., Toro, L. (2008). c-Src tyrosine kinase, a critical component for 5-HT2A receptor-mediated contraction in rat aorta. J. Physiol. 586: 3855-3869 [Abstract] [Full Text]  
• Rovati, G. E., Capra, V., Neubig, R. R. (2007). The Highly Conserved DRY Motif of Class A G Protein-Coupled Receptors: Beyond the Ground State. Mol. Pharmacol. 71: 959-964 [Abstract] [Full Text]  
• Leung, P. C.K., Choi, J.-H. (2007). Endocrine signaling in ovarian surface epithelium and cancer. Hum Reprod Update 13: 143-162 [Abstract] [Full Text]  
• Vroon, A., Heijnen, C. J., Kavelaars, A. (2006). GRKs and arrestins: regulators of migration and inflammation. J. Leukoc. Biol. 80: 1214-1221 [Abstract] [Full Text]  
• Xu, Q., Xu, N., Zhang, T., Zhang, H., Li, Z., Yin, F., Lu, Z., Han, Q., Zhang, Y. (2006). Mammalian Tolloid Alters Subcellular Localization, Internalization, and Signaling of {alpha}1a-Adrenergic Receptors. Mol. Pharmacol. 70: 532-541 [Abstract] [Full Text]  
• Macdonald, D. S., Weerapura, M., Beazely, M. A., Martin, L., Czerwinski, W., Roder, J. C., Orser, B. A., MacDonald, J. F. (2005). Modulation of NMDA Receptors by Pituitary Adenylate Cyclase Activating Peptide in CA1 Neurons Requires G{alpha}q, Protein Kinase C, and Activation of Src. J. Neurosci. 25: 11374-11384 [Abstract] [Full Text]  
• Li, J., Dai, Z., Jana, D., Callaway, D. J. E., Bu, Z. (2005). Ezrin Controls the Macromolecular Complexes Formed between an Adapter Protein Na+/H+ Exchanger Regulatory Factor and the Cystic Fibrosis Transmembrane Conductance Regulator. J. Biol. Chem. 280: 37634-37643 [Abstract] [Full Text]  
• Gage, R. M., Matveeva, E. A., Whiteheart, S. W., von Zastrow, M. (2005). Type I PDZ Ligands Are Sufficient to Promote Rapid Recycling of G Protein-coupled Receptors Independent of Binding to N-Ethylmaleimide-sensitive Factor. J. Biol. Chem. 280: 3305-3313 [Abstract] [Full Text]  
• Yang, L. V., Radu, C. G., Wang, L., Riedinger, M., Witte, O. N. (2005). Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood 105: 1127-1134 [Abstract] [Full Text]  
• Xiao, K., Shenoy, S. K., Nobles, K., Lefkowitz, R. J. (2004). Activation-dependent Conformational Changes in {beta}-Arrestin 2. J. Biol. Chem. 279: 55744-55753 [Abstract] [Full Text]  
• Voronina, E., Wessel, G. M. (2004). {beta}{gamma} subunits of heterotrimeric G-proteins contribute to Ca2+ release at fertilization in the sea urchin. J. Cell Sci. 117: 5995-6005 [Abstract] [Full Text]  
• Kukita, T., Wada, N., Kukita, A., Kakimoto, T., Sandra, F., Toh, K., Nagata, K., Iijima, T., Horiuchi, M., Matsusaki, H., Hieshima, K., Yoshie, O., Nomiyama, H. (2004). RANKL-induced DC-STAMP Is Essential for Osteoclastogenesis. JEM 200: 941-946 [Abstract] [Full Text]  
• Ahn, S., Shenoy, S. K., Wei, H., Lefkowitz, R. J. (2004). Differential Kinetic and Spatial Patterns of {beta}-Arrestin and G Protein-mediated ERK Activation by the Angiotensin II Receptor. J. Biol. Chem. 279: 35518-35525 [Abstract] [Full Text]  
• Breit, A., Lagace, M., Bouvier, M. (2004). Hetero-oligomerization between {beta}2- and {beta}3-Adrenergic Receptors Generates a {beta}-Adrenergic Signaling Unit with Distinct Functional Properties. J. Biol. Chem. 279: 28756-28765 [Abstract] [Full Text]  
• Revankar, C. M., Vines, C. M., Cimino, D. F., Prossnitz, E. R. (2004). Arrestins Block G Protein-coupled Receptor-mediated Apoptosis. J. Biol. Chem. 279: 24578-24584 [Abstract] [Full Text]  
• Pandey, S., Assmann, S. M. (2004). The Arabidopsis Putative G Protein-Coupled Receptor GCR1 Interacts with the G Protein {alpha} Subunit GPA1 and Regulates Abscisic Acid Signaling. Plant Cell 16: 1616-1632 [Abstract] [Full Text]  
• Chen, J.-G., Pandey, S., Huang, J., Alonso, J. M., Ecker, J. R., Assmann, S. M., Jones, A. M. (2004). GCR1 Can Act Independently of Heterotrimeric G-Protein in Response to Brassinosteroids and Gibberellins in Arabidopsis Seed Germination. Plant Physiol. 135: 907-915 [Abstract] [Full Text]  
• Little, K. D., Hemler, M. E., Stipp, C. S. (2004). Dynamic Regulation of a GPCR-Tetraspanin-G Protein Complex on Intact Cells: Central Role of CD81 in Facilitating GPR56-G{alpha}q/11 Association. Mol. Biol. Cell 15: 2375-2387 [Abstract] [Full Text]  
• Borkovich, K. A., Alex, L. A., Yarden, O., Freitag, M., Turner, G. E., Read, N. D., Seiler, S., Bell-Pedersen, D., Paietta, J., Plesofsky, N., Plamann, M., Goodrich-Tanrikulu, M., Schulte, U., Mannhaupt, G., Nargang, F. E., Radford, A., Selitrennikoff, C., Galagan, J. E., Dunlap, J. C., Loros, J. J., Catcheside, D., Inoue, H., Aramayo, R., Polymenis, M., Selker, E. U., Sachs, M. S., Marzluf, G. A., Paulsen, I., Davis, R., Ebbole, D. J., Zelter, A., Kalkman, E. R., O'Rourke, R., Bowring, F., Yeadon, J., Ishii, C., Suzuki, K., Sakai, W., Pratt, R. (2004). Lessons from the Genome Sequence of Neurospora crassa: Tracing the Path from Genomic Blueprint to Multicellular Organism. Microbiol. Mol. Biol. Rev. 68: 1-108 [Abstract] [Full Text]  
• Fuxe, K., Agnati, L.F., Jacobsen, K., Hillion, J., Canals, M., Torvinen, M., Tinner-Staines, B., Staines, W., Rosin, D., Terasmaa, A., Popoli, P., Leo, G., Vergoni, V., Lluis, C., Ciruela, F., Franco, R., Ferre, S. (2003). Receptor heteromerization in adenosine A2A receptor signaling: Relevance for striatal function and Parkinson's disease. Neurology 61: S19-23 [Abstract] [Full Text]  
• Lopez-Ilasaca, M., Liu, X., Tamura, K., Dzau, V. J. (2003). The Angiotensin II Type I Receptor-associated Protein, ATRAP, Is a Transmembrane Protein and a Modulator of Angiotensin II Signaling. Mol. Biol. Cell 14: 5038-5050 [Abstract] [Full Text]  
• Okuno, T., Ago, H., Terawaki, K., Miyano, M., Shimizu, T., Yokomizo, T. (2003). Helix 8 of the Leukotriene B4 Receptor Is Required for the Conformational Change to the Low Affinity State after G-protein Activation. J. Biol. Chem. 278: 41500-41509 [Abstract] [Full Text]  
• Bosche, L. I, Wellner-Kienitz, M.-C., Bender, K., Pott, L. (2003). G Protein-Independent Inhibition of GIRK Current by Adenosine in Rat Atrial Myocytes Overexpressing A1 Receptors after Adenovirus-Mediated Gene Transfer. J. Physiol. 550: 707-717 [Abstract] [Full Text]  
• Gettemans, J., Meerschaert, K., Vandekerckhove, J., De Corte, V. (2003). A Kelch {beta} Propeller Featuring as a G{beta} Structural Mimic: Reinventing the Wheel?. Sci Signal 2003: pe27-pe27 [Abstract] [Full Text]  
• Hu, L. A., Chen, W., Martin, N. P., Whalen, E. J., Premont, R. T., Lefkowitz, R. J. (2003). GIPC Interacts with the {beta}1-Adrenergic Receptor and Regulates {beta}1-Adrenergic Receptor-mediated ERK Activation. J. Biol. Chem. 278: 26295-26301 [Abstract] [Full Text]  
• Lam, R. S, App, E. M, Nahirney, D., Szkotak, A. J, Vieira-Coelho, M. A, King, M., Duszyk, M. (2003). Regulation of Cl- secretion by {alpha}2-adrenergic receptors in mouse colonic epithelium. J. Physiol. 548: 475-484 [Abstract] [Full Text]  
• Windmiller, D. A., Backer, J. M. (2003). Distinct Phosphoinositide 3-Kinases Mediate Mast Cell Degranulation in Response to G-protein-coupled Versus Fcepsilon RI Receptors. J. Biol. Chem. 278: 11874-11878 [Abstract] [Full Text]  
• Seck, T., Baron, R., Horne, W. C. (2003). Binding of Filamin to the C-terminal Tail of the Calcitonin Receptor Controls Recycling. J. Biol. Chem. 278: 10408-10416 [Abstract] [Full Text]  
• Brink, C., Dahlen, S.-E., Drazen, J., Evans, J. F., Hay, D. W. P., Nicosia, S., Serhan, C. N., Shimizu, T., Yokomizo, T. (2003). International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors. Pharmacol. Rev. 55: 195-227 [Abstract] [Full Text]  
• Ahn, S., Nelson, C. D., Garrison, T. R., Miller, W. E., Lefkowitz, R. J. (2003). Desensitization, internalization, and signaling functions of beta -arrestins demonstrated by RNA interference. Proc. Natl. Acad. Sci. USA 100: 1740-1744 [Abstract] [Full Text]  
• Kurrasch-Orbaugh, D. M., Watts, V. J., Barker, E. L., Nichols, D. E. (2003). Serotonin 5-Hydroxytryptamine2A Receptor-Coupled Phospholipase C and Phospholipase A2 Signaling Pathways Have Different Receptor Reserves. J. Pharmacol. Exp. Ther. 304: 229-237 [Abstract] [Full Text]  
• Benquet, P., Gee, C. E., Gerber, U. (2002). Two Distinct Signaling Pathways Upregulate NMDA Receptor Responses via Two Distinct Metabotropic Glutamate Receptor Subtypes. J. Neurosci. 22: 9679-9686 [Abstract] [Full Text]  
• Hall, R. A., Lefkowitz, R. J. (2002). Regulation of G Protein-Coupled Receptor Signaling by Scaffold Proteins. Circ. Res. 91: 672-680 [Abstract] [Full Text]  
• Lynch, R. A., Wagoner, L., Li, S., Sparks, L., Molkentin, J., Dorn, G. W. II (2002). Novel and nondetected human signaling protein polymorphisms. Physiol. Genomics 10: 159-168 [Abstract] [Full Text]  
• Zhu, Y., Hon, T., Ye, W., Zhang, L. (2002). Heme Deficiency Interferes with the Ras-Mitogen-activated Protein Kinase Signaling Pathway and Expression of a Subset of Neuronal Genes. Cell Growth Differ. 13: 431-439 [Abstract] [Full Text]  
• Hollinger, S., Hepler, J. R. (2002). Cellular Regulation of RGS Proteins: Modulators and Integrators of G Protein Signaling. Pharmacol. Rev. 54: 527-559 [Abstract] [Full Text]  
• McClatchy, D. B., Knudsen, C. R., Clark, B. F., Kahn, R. A., Hall, R. A., Levey, A. I. (2002). Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2. J. Biol. Chem. 277: 29268-29274 [Abstract] [Full Text]  
• Li, J.-G., Chen, C., Liu-Chen, L.-Y. (2002). Ezrin-Radixin-Moesin-binding Phosphoprotein-50/Na+/H+ Exchanger Regulatory Factor (EBP50/NHERF) Blocks U50,488H-induced Down-regulation of the Human kappa Opioid Receptor by Enhancing Its Recycling Rate. J. Biol. Chem. 277: 27545-27552 [Abstract] [Full Text]  
• Dumont, J. E., Dremier, S., Pirson, I., Maenhaut, C. (2002). Cross signaling, cell specificity, and physiology. Am. J. Physiol. Cell Physiol. 283: C2-C28 [Abstract] [Full Text]  
• Sorensen, S. D., Macek, T. A., Cai, Z., Saugstad, J. A., Conn, P. J. (2002). Dissociation of Protein Kinase-Mediated Regulation of Metabotropic Glutamate Receptor 7 (mGluR7) Interactions with Calmodulin and Regulation of mGluR7 Function. Mol. Pharmacol. 61: 1303-1312 [Abstract] [Full Text]  
• Lowe, J. D., Celver, J. P., Gurevich, V. V., Chavkin, C. (2002). {micro}-Opioid Receptors Desensitize Less Rapidly than delta -Opioid Receptors Due to Less Efficient Activation of Arrestin. J. Biol. Chem. 277: 15729-15735 [Abstract] [Full Text]  
• Assmann, S. M. (2002). Heterotrimeric and Unconventional GTP Binding Proteins in Plant Cell Signaling. Plant Cell 14: S355-373 [Full Text]  
• Ascoli, M., Fanelli, F., Segaloff, D. L. (2002). The Lutropin/Choriogonadotropin Receptor, A 2002 Perspective. Endocr. Rev. 23: 141-174 [Abstract] [Full Text]  
• Seta, K., Nanamori, M., Modrall, J. G., Neubig, R. R., Sadoshima, J. (2002). AT1 Receptor Mutant Lacking Heterotrimeric G Protein Coupling Activates the Src-Ras-ERK Pathway without Nuclear Translocation of ERKs. J. Biol. Chem. 277: 9268-9277 [Abstract] [Full Text]  
• Hirakawa, T., Galet, C., Ascoli, M. (2002). MA-10 Cells Transfected with the Human Lutropin/Choriogonadotropin Receptor (hLHR): A Novel Experimental Paradigm to Study the Functional Properties of the hLHR. Endocrinology 143: 1026-1035 [Abstract] [Full Text]  
• Peavy, R. D., Chang, M. S. S., Sanders-Bush, E., Conn, P. J. (2001). Metabotropic Glutamate Receptor 5-Induced Phosphorylation of Extracellular Signal-Regulated Kinase in Astrocytes Depends on Transactivation of the Epidermal Growth Factor Receptor. J. Neurosci. 21: 9619-9628 [Abstract] [Full Text]  
• Sánchez, C., Rueda, D., Ségui, B., Galve-Roperh, I., Levade, T., Guzmán, M. (2001). The CB1 Cannabinoid Receptor of Astrocytes Is Coupled to Sphingomyelin Hydrolysis through the Adaptor Protein Fan. Mol. Pharmacol. 59: 955-959 [Abstract] [Full Text]  
• Ferguson, S. S. G. (2001). Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling. Pharmacol. Rev. 53: 1-24 [Abstract] [Full Text]  
• Milligan, G (2001). Oligomerisation of G-protein-coupled receptors. J. Cell Sci. 114: 1265-1271 [Abstract]  
• Rao, R. V., Holicky, E. L., Kuntz, S. M., Miller, L. J. (2000). CCK receptor phosphorylation exposes regulatory domains affecting phosphorylation and receptor trafficking. Am. J. Physiol. Cell Physiol. 279: C1986-C1992 [Abstract] [Full Text]  
• Esposito, G., Santana, L. F., Dilly, K., Cruz, J. D. S., Mao, L., Lederer, W. J., Rockman, H. A. (2000). Cellular and functional defects in a mouse model of heart failure. Am. J. Physiol. Heart Circ. Physiol. 279: H3101-H3112 [Abstract] [Full Text]  
• Wilson, B. A., Aminova, L. R., Ponferrada, V. G., Ho, M. (2000). Differential Modulation and Subsequent Blockade of Mitogenic Signaling and Cell Cycle Progression by Pasteurella multocida Toxin. Infect. Immun. 68: 4531-4538 [Abstract] [Full Text]  
• Mackenzie, J. F., Daly, C. J., Pediani, J. D., McGrath, J. C. (2000). Quantitative Imaging in Live Human Cells Reveals Intracellular alpha 1-Adrenoceptor Ligand-Binding Sites. J. Pharmacol. Exp. Ther. 294: 434-443 [Abstract] [Full Text]  
• Francesconi, A., Duvoisin, R. M. (2000). Opposing effects of protein kinase C and protein kinase A on metabotropic glutamate receptor signaling: Selective desensitization of the inositol trisphosphate/Ca2+ pathway by phosphorylation of the receptor-G protein-coupling domain. Proc. Natl. Acad. Sci. USA 97: 6185-6190 [Abstract] [Full Text]  
• Li, S., Liu, X., Ascoli, M. (2000). p38JAB1 Binds to the Intracellular Precursor of the Lutropin/Choriogonadotropin Receptor and Promotes Its Degradation. J. Biol. Chem. 275: 13386-13393 [Abstract] [Full Text]  
• Kobilka, B. (2000). Allosteric activation of the CaR by L-amino acids. Proc. Natl. Acad. Sci. USA 97: 4419-4420 [Full Text]  
• Miller, W. E., Maudsley, S., Ahn, S., Khan, K. D., Luttrell, L. M., Lefkowitz, R. J. (2000). beta -Arrestin1 Interacts with the Catalytic Domain of the Tyrosine Kinase c-SRC. ROLE OF beta -ARRESTIN1-DEPENDENT TARGETING OF c-SRC IN RECEPTOR ENDOCYTOSIS. J. Biol. Chem. 275: 11312-11319 [Abstract] [Full Text]  
• Manivet, P., Mouillet-Richard, S., Callebert, J., Nebigil, C. G., Maroteaux, L., Hosoda, S., Kellermann, O., Launay, J.-M. (2000). PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor. J. Biol. Chem. 275: 9324-9331 [Abstract] [Full Text]  
• Lee, H.-J., Chun, M., Kandror, K. V. (2001). Tip60 and HDAC7 Interact with the Endothelin Receptor A and May Be Involved in Downstream Signaling. J. Biol. Chem. 276: 16597-16600 [Abstract] [Full Text]  
• Demchyshyn, L. L., McConkey, F., Niznik, H. B. (2000). Dopamine D5 Receptor Agonist High Affinity and Constitutive Activity Profile Conferred by Carboxyl-terminal Tail Sequence. J. Biol. Chem. 275: 23446-23455 [Abstract] [Full Text]  
• Horie, K., Insel, P. A. (2000). Retrovirally Mediated Transfer of a G Protein-coupled Receptor Kinase (GRK) Dominant-negative Mutant Enhances Endogenous Calcitonin Receptor Signaling in Chinese Hamster Ovary Cells. GRK INHIBITION ENHANCES EXPRESSION OF RECEPTORS AND RECEPTOR mRNA. J. Biol. Chem. 275: 29433-29440 [Abstract] [Full Text]  
• Fan, X., Brass, L. F., Poncz, M., Spitz, F., Maire, P., Manning, D. R. (2000). The alpha Subunits of Gz and Gi Interact with the eyes absent Transcription Cofactor Eya2, Preventing Its Interaction with the Six Class of Homeodomain-containing Proteins. J. Biol. Chem. 275: 32129-32134 [Abstract] [Full Text]  
• Benard, O., Naor, Z., Seger, R. (2001). Role of Dynamin, Src, and Ras in the Protein Kinase C-mediated Activation of ERK by Gonadotropin-releasing Hormone. J. Biol. Chem. 276: 4554-4563 [Abstract] [Full Text]  
• Ghalayini, A. J., Desai, N., Smith, K. R., Holbrook, R. M., Elliott, M. H., Kawakatsu, H. (2002). Light-dependent Association of Src with Photoreceptor Rod Outer Segment Membrane Proteins in Vivo. J. Biol. Chem. 277: 1469-1476 [Abstract] [Full Text]  
• Awata, H., Huang, C., Handlogten, M. E., Miller, R. T. (2001). Interaction of the Calcium-sensing Receptor and Filamin, a Potential Scaffolding Protein. J. Biol. Chem. 276: 34871-34879 [Abstract] [Full Text]  
• Percherancier, Y., Planchenault, T., Valenzuela-Fernandez, A., Virelizier, J.-L., Arenzana-Seisdedos, F., Bachelerie, F. (2001). Palmitoylation-dependent Control of Degradation, Life Span, and Membrane Expression of the CCR5 Receptor. J. Biol. Chem. 276: 31936-31944 [Abstract] [Full Text]  
• Cong, M., Perry, S. J., Hu, L. A., Hanson, P. I., Claing, A., Lefkowitz, R. J. (2001). Binding of the beta 2 Adrenergic Receptor to N-Ethylmaleimide-sensitive Factor Regulates Receptor Recycling. J. Biol. Chem. 276: 45145-45152 [Abstract] [Full Text]  

This Article Full Text (PDF, 148K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hall, R. A. Articles by Lefkowitz, R. J. Search for Related Content PubMed PubMed Citation Articles by Hall, R. A. Articles by Lefkowitz, R. J. Social Bookmarking                            What's this?