Agonist-independent inhibition of G protein activation by muscarinic acetylcholine receptor antagonists in cardiac membranes

Eur J Pharmacol. 1992 Mar 12;225(3):245-52. doi: 10.1016/0922-4106(92)90026-r.


Agonist activation of muscarinic acetylcholine (mACh) receptors in porcine atrial membranes stimulates binding of the GTP analog, guanosine 5'-O-[gamma-thio]triphosphate (GTP[S]), to membrane G proteins. In contrast, atropine as well as several other mACh receptor antagonists reduced the binding of GTP[S] below basal values, both in the absence and presence of the agonist carbachol, by a similar maximal extent (about 25%). Evidence is presented that this inhibitory action of atropine was not due to an antagonism of endogenous acetylcholine. Similar to agonist-induced stimulation, antagonist-induced inhibition of GTP[S] binding required the presence of GDP and Mg2+. On the other hand, addition of salts, e.g. NaCl, amplified agonist but reduced antagonist effects on GTP[S] binding. The data presented suggest that agonist-unliganded mACh receptors interact with and activate G proteins in native cardiac membranes and that antagonist binding induces a conformational change of the receptor, which then either does not interact with G proteins or which prevents GDP release from and subsequent GTP[S] binding to G proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / pharmacology
  • Animals
  • Atropine / pharmacology
  • Biotransformation / drug effects
  • Carbachol / pharmacology
  • GTP-Binding Proteins / metabolism*
  • Guanosine 5'-O-(3-Thiotriphosphate) / analogs & derivatives
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
  • In Vitro Techniques
  • Magnesium / pharmacology
  • Membranes / metabolism
  • Muscarinic Antagonists*
  • Myocardium / metabolism*
  • Protein Binding
  • Receptors, Muscarinic / drug effects
  • Swine


  • Muscarinic Antagonists
  • Receptors, Muscarinic
  • guanosine 5'-O-(2-thiotriphosphate)
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Atropine
  • Carbachol
  • Acetylcholinesterase
  • GTP-Binding Proteins
  • Magnesium