Phosphotidylinositol 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels

Nikita Gamper, Vitaliy Reznikov, Yoichi Yamada, Jian Yang, Mark S. Shapiro

Research output: Contribution to journalArticle

169 Scopus citations

Abstract

Modulation of voltage-gated Ca2+ channels via G-protein-coupled receptors is a prime mechanism regulating neurotransmitter release and synaptic plasticity. Despite extensive studies, the molecular mechanism underlying G q/11-mediated modulation remains unclear. We found cloned and native N-type Ca2+ channels to be regulated by phosphotidylinositol 4,5-bisphosphate (PIP2). In inside-out oocyte patches, PIP 2 greatly attenuated or reversed the observed rundown of expressed channels. In sympathetic neurons, muscarinic M1 ACh receptor suppression of the Ca2+ current (ICa) was temporally correlated with PIP2 hydrolysis, blunted by PIP2 in whole-cell pipettes, attenuated by expression of PIP2-sequestering proteins, and became irreversible when PIP2 synthesis was blocked. We also probed mechanisms of receptor specificity. Although bradykinin also induced PIP2 hydrolysis, it did not inhibit ICa. However, bradykinin receptors became nearly as effective as M1 receptors when PIP2 synthesis, IP3 receptors, or the activity of neuronal Ca2+ sensor-1 were blocked, suggesting that bradykinin receptor-induced intracellular Ca2+ increases stimulate PIP 2 synthesis, compensating for PIP2 hydrolysis. We suggest that differential use of PIP2 signals underlies specificity of G q/11-coupled receptor actions on the channels.

Original languageEnglish (US)
Pages (from-to)10980-10992
Number of pages13
JournalJournal of Neuroscience
Volume24
Issue number48
DOIs
StatePublished - Dec 1 2004

Keywords

  • Bradykinin
  • Calcium channel
  • G-protein
  • Lipid signaling
  • Muscarinic receptor
  • Patch clamp

ASJC Scopus subject areas

  • Neuroscience(all)

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