Distinct sequence elements control the specificity of G protein activation by muscarinic acetylcholine receptor subtypes

J. Lechleiter, R. Hellmiss, K. Duerson, D. Ennulat, N. David, D. Clapham, E. Peralta

Research output: Contribution to journalArticlepeer-review

148 Scopus citations

Abstract

Relatively little is understood concerning the mechanisms by which types of receptors, G proteins and effector enzymes interact to transduce specific signals. Through expression of normal, hybrid and deletion mutant receptors in Xenopus oocytes, we determined the G protein coupling characteristics of the functionally distinct m2 and m3 muscarinic acetylcholine receptor (mAChR) subtypes and identified the critical receptor sequences responsible for G protein specificity. Activation of a pertussis toxin insensitive G protein pathway, leading to a rapid and transient release of intracellular Ca2+ characteristic of the m3 receptor, could be specified by the transfer of as few as nine amino acids from the m3 to the m2 receptor. In a reciprocal manner, transfer of no more than 21 residues from the m2 to the m3 receptor was sufficient to specify activation of a pertussis toxin sensitive G protein coupled to a slow and oscillatory Ca2+ release pathway typical of the m2 subtype. Notably, these critical residues occur within the same region of the third cytoplasmic domain of functionally distinct mAChR subtypes.

Original languageEnglish (US)
Pages (from-to)4381-4390
Number of pages10
JournalEMBO Journal
Volume9
Issue number13
DOIs
StatePublished - 1990

Keywords

  • G protein selectivity
  • ion channels
  • muscarinic receptors

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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