Muscarinic inhibition of nicotinic transmission in rat sympathetic neurons and adrenal chromaffin cells

Philos Trans R Soc Lond B Biol Sci. 2015 Jul 5;370(1672):20140188. doi: 10.1098/rstb.2014.0188.


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.

Keywords: G-proteins; mAchRs; methacholine; nAchRs; nicotine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromaffin Cells / metabolism
  • Chromaffin Cells / physiology*
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • GTP-Binding Proteins / metabolism
  • Methacholine Chloride / pharmacology*
  • Muscarinic Agonists / pharmacology
  • Neurons / metabolism
  • Neurons / physiology*
  • Nicotinic Antagonists / pharmacology*
  • Patch-Clamp Techniques
  • Protein Kinase C / antagonists & inhibitors
  • Rats
  • Second Messenger Systems / physiology
  • Superior Cervical Ganglion / cytology*
  • Superior Cervical Ganglion / physiology
  • Synaptic Transmission / physiology*
  • Temperature
  • Time Factors


  • Muscarinic Agonists
  • Nicotinic Antagonists
  • Methacholine Chloride
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • GTP-Binding Proteins