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Selective coupling of type 6 adenylyl cyclase with type 2 IP₃ receptors mediates direct sensitization of IP₃ receptors by cAMP

Department of Pharmacology, Univesrsity of Cambridge, Cambridge CB2 1PD, England, UK

Correspondence to Colin W. Taylor: cwt1000{at}cam.ac.uk

Interactions between cyclic adenosine monophosphate (cAMP) and Ca²⁺ are widespread, and for both intracellular messengers, their spatial organization is important. Parathyroid hormone (PTH) stimulates formation of cAMP and sensitizes inositol 1,4,5-trisphosphate receptors (IP₃R) to IP₃. We show that PTH communicates with IP₃R via "cAMP junctions" that allow local delivery of a supramaximal concentration of cAMP to IP₃R, directly increasing their sensitivity to IP₃. These junctions are robust binary switches that are digitally recruited by increasing concentrations of PTH. Human embryonic kidney cells express several isoforms of adenylyl cyclase (AC) and IP₃R, but IP₃R2 and AC6 are specifically associated, and inhibition of AC6 or IP₃R2 expression by small interfering RNA selectively attenuates potentiation of Ca²⁺ signals by PTH. We define two modes of cAMP signaling: binary, where cAMP passes directly from AC6 to IP₃R2; and analogue, where local gradients of cAMP concentration regulate cAMP effectors more remote from AC. Binary signaling requires localized delivery of cAMP, whereas analogue signaling is more dependent on localized cAMP degradation.

Abbreviations used in this paper: AC, adenylyl cyclase; AKAP, A kinase–anchoring protein; CCh, carbachol; CNGC, cyclic nucleotide-gated cation channel; DDA, 2',5'-dideoxyadenosine; epac, exchange protein activated by cAMP; FK, forskolin; HBS, Hepes-buffered saline; HEK, human embryonic kidney; HEK-PR1, HEK cells stably expressing human type I PTH receptors; IBMX, 3-isobutyl-1-methylxanthine; IP, immunoprecipitation; IP₃, inositol 1,4,5-trisphosphate; IP₃R, IP₃ receptor; PDE, phosphodiesterase; PGE₁, prostaglandin E₁; PKA, protein kinase A; PTH, parathyroid hormone; QPCR, quantitative PCR; RpcAMPS, adenosine 3',5'-cyclic phosphorothioate-Rp; SERCA, SR/ER Ca²⁺-ATPase; SQ 22536, 9-(tetrahydro-2'-furyl)adenine; SR, sarcoplasmic reticulum; WB, Western blot.

© 2008 Tovey et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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