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J. Cell Biol. 192 (1): 137-151

Copyright © 2011 by the Rockefeller University Press.

Article

A novel fast mechanism for GPCR-mediated signal transduction—control of neurotransmitter release

Yonatan M. Kupchik1, Ofra Barchad-Avitzur1, Jürgen Wess2, Yair Ben-Chaim1, Itzchak Parnas1, , and Hanna Parnas1

1 Department of Neurobiology, Institute of Life Sciences, The Edmond Safra campus, The Hebrew University, Jerusalem 91904, Israel
2 Molecular Signalling Section and Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Correspondence to Hanna Parnas: hannap{at}huji.ac.il

Abstract: Reliable neuronal communication depends on accurate temporal correlation between the action potential and neurotransmitter release. Although a requirement for Ca2+ in neurotransmitter release is amply documented, recent studies have shown that voltage-sensitive G protein–coupled receptors (GPCRs) are also involved in this process. However, how slow-acting GPCRs control fast neurotransmitter release is an unsolved question. Here we examine whether the recently discovered fast depolarization-induced charge movement in the M2-muscarinic receptor (M2R) is responsible for M2R-mediated control of acetylcholine release. We show that inhibition of the M2R charge movement in Xenopus oocytes correlated well with inhibition of acetylcholine release at the mouse neuromuscular junction. Our results suggest that, in addition to Ca2+ influx, charge movement in GPCRs is also necessary for release control.

Abbreviations: ACh, acetylcholine • CCh, carbachol • CNB-carbachol, N-({alpha}-carboxy-2nitrobenzyl) carbamylcholine • DI, dose inhibition • ENTC, excitatory nerve terminal current • EPSC, excitatory postsynaptic current • Gal, gallamine • GC, gating current • GIRK, G protein–activated inwardly rectifying K+ current • GPCR, G protein–coupled receptor • IC50, half maximal inhibitory concentration • M2KO, M2R knockout • M2R, M2-muscarinic receptor • Meth, methoctramine • mGluR, metabotropic glutamate receptor • NMJ, neuromuscular junction • TTX, tetrodotoxin • WT, wild type

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