Distinct sites on G protein βγ subunits regulate different effector functions

Tooraj Mirshahi, Vivek Mittal, Hailin Zhang, Maurine E. Linder, Diomedes E. Logothetis

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

G proteins interact with effectors at multiple sites and regulate their activity. The functional significance of multiple contact points is not well understood. We previously identified three residues on distinct surfaces of Gβγ that are crucial for G protein-coupled inward rectifier K + (GIRK) channel activation. Here we show that mutations at these sites, S67K, S98T, and T128F, abolished or reduced direct GIRK current activation in inside-out patches, but, surprisingly, all mutants synergized with sodium in activating K + currents. Each of the three Gβ 1 mutants bound the channel indicating that the defects reflected mainly functional impairments. We tested these mutants for functional interactions with effectors other than K + channels. With N-type calcium channels, Gβγ wild type and mutants all inhibited basal currents. A depolarizing pre-pulse relieved Gβγ inhibition of Ca 2+ currents by the wild type and the S98T and T128F mutants but not the S67K mutant. Both wild type and mutant Gβγ subunits activated phospholipase C β 2 with similar potencies; however, the S67K mutant showed reduced maximal activity. These data establish a pattern where mutations can alter the Gβγ regulation of a specific effector function without affecting other Gβγ-mediated functions. Moreover, Ser-67 showed this pattern in all three effectors tested, suggesting that this residue participates in a common functional domain on Gβ 1 that regulates several effectors. These data show that distinct domains within Gβγ subserve specific functional roles.

Original languageEnglish (US)
Pages (from-to)36345-36350
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number39
DOIs
StatePublished - Sep 27 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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