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Presynaptic Type III Neuregulin1-ErbB signaling targets 7 nicotinic acetylcholine receptors to axons

¹ Integrated Program in Cellular, Molecular and Biophysical Studies, ² Department of Neurosciences, ³ Department of Pathology and Cell Biology, and ⁴ The Institute of Human Nutrition, Columbia University, New York, NY 10032

Correspondence to David A. Talmage: talmage{at}pharm.stonybrook.edu

Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of 7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface 7 nAChRs, which results from a redistribution of preexisting intracellular pools of 7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting 7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function.

L.W. Role's present address is Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794.

D.A. Talmage's present address is Department of Pharmacological Science and Center for Brain and Spinal Cord Research, State University of New York at Stony Brook, Stony Brook, NY 11794.

Abbreviations used in this paper: AFI, average fluorescence intensity; Akt inh., Akt inhibitor; a.u., arbitrary units; CHX, cycloheximide; DRG, dorsal root ganglia; E, embryonic day; ECD, extracellular domain; nAChR, nicotinic acetylcholine receptor; NF, neurofilament; Nrg1, Neuregulin1; PAO, phenylarsine oxide; PIP₃, phosphatidylinositol 3,4,5 trisphosphate; PtdIns 3K, phosphatidylinositol 3-kinase; vGlut1, vesicular glutamate transporter 1; WM, wortmannin; WT, wild type.

© 2008 Hancock 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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This article has been cited by other articles:

• Zhong, C., Du, C., Hancock, M., Mertz, M., Talmage, D. A., Role, L. W. (2008). Presynaptic Type III Neuregulin 1 Is Required for Sustained Enhancement of Hippocampal Transmission by Nicotine and for Axonal Targeting of {alpha}7 Nicotinic Acetylcholine Receptors. J. Neurosci. 28: 9111-9116 [Abstract] [Full Text]  
• Hancock, M. L., Canetta, S. E., Role, L. W., Talmage, D. A. (2008). Presynaptic type III neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons. JGP 131: i4-i4 [Full Text]  

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