title: Muscarinic inhibition of nicotinic transmission in rat sympathetic neurons and adrenal chromaffin cells.
abstract: Little is known about the interactions between nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs). Here we report that methacholine (MCh), a selective agonist of mAChRs, inhibited up to 80% of nicotine-induced nAChR currents in sympathetic superior cervical ganglion neurons and adrenal chromaffin cells. The muscarine-induced inhibition (MiI) substantially reduced ACh-induced membrane currents through nAChRs and quantal neurotransmitter release. The MiI was time- and temperature-dependent. The slow recovery of nAChR current after washout of MCh, as well as the high value of Q10 (3.2), suggested, instead of a direct open-channel blockade, an intracellular metabotropic process. The effects of GTP-γ-S, GDP-β-S and pertussis toxin suggested that MiI was mediated by G-protein signalling. Inhibitors of protein kinase C (bisindolymaleimide-Bis), protein kinase A (H89) and PIP2 depletion attenuated the MiI, indicating that a second messenger pathway is involved in this process. Taken together, these data suggest that mAChRs negatively modulated nAChRs via a G-protein-mediated second messenger pathway. The time dependence suggests that MiI may provide a novel mechanism for post-synaptic adaptation in all cells/neurons and synapses expressing both types of AChRs.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and PKU-IDG/McGovern Institute for Brain Research and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, People's Republic of China Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Lin-Ling
authors.initials: LL
authors.lastname: He
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and PKU-IDG/McGovern Institute for Brain Research and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, People's Republic of China.
authors.forename: Quan-Feng
authors.initials: QF
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and PKU-IDG/McGovern Institute for Brain Research and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, People's Republic of China.
authors.forename: Lie-Cheng
authors.initials: LC
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and PKU-IDG/McGovern Institute for Brain Research and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, People's Republic of China.
authors.forename: Jing-Xia
authors.initials: JX
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and PKU-IDG/McGovern Institute for Brain Research and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, People's Republic of China.
authors.forename: Chang-He
authors.initials: CH
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and PKU-IDG/McGovern Institute for Brain Research and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, People's Republic of China lhzheng@pku.edu.cn.
authors.forename: Liang-Hong
authors.initials: LH
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and PKU-IDG/McGovern Institute for Brain Research and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, People's Republic of China zzhou@pku.edu.cn.
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D019439:Chromaffin Cells / Q000378:metabolism / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D019204:GTP-Binding Proteins / Q000378:metabolism; D016210:Methacholine Chloride / Q000494:pharmacology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D015290:Second Messenger Systems / Q000502:physiology; D017783:Superior Cervical Ganglion / Q000166:cytology* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D013696:Temperature; D013997:Time Factors
chemical_list: D018721:Muscarinic Agonists; D018733:Nicotinic Antagonists; D016210:Methacholine Chloride; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019204:GTP-Binding Proteins
keywords: G-proteins; mAchRs; methacholine; nAchRs; nicotine