Combined phosphoinositide and Ca2+ signals mediating receptor specificity toward neuronal Ca2+ channels

Oleg Zaika, Jie Zhang, Mark S. Shapiro

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates Ca 2+ (ICa) and M-type K+ currents in superior cervical ganglion sympathetic neurons. In those cells,M1 muscarinic and AT1 angiotensin types do not elicit Ca2+i signals and suppress both currents via depletion of PIP2, whereas the B2 bradykinin and P2Y purinergic types elicit robust IP 3-mediated [Ca2+]i rises and neither deplete PIP2 nor inhibit ICa. We have suggested that this specificity arises from differential Ca2+i signals underlying receptor-specific stimulation of PIP2 synthesis by phosphatidylinositol (PI) 4-kinase. Here, we investigate which PI 4-kinase isoform underlies this signal, whether stimulation of PI 4-phosphate 5-kinase is also required, and the origin of receptor-specific Ca2+i signals. Recordings of ICa were used as a PIP2 "biosensor." In control, stimulation of M1, but not B2 or P2Y, receptors robustly suppressed ICa. However, when PI 4-kinase IIIβ, diacylglycerol kinase, Rho, or Rho-kinase was blocked, agonists of all three receptors robustly suppressed ICa. Overexpression of exogenous M1 receptors yielded large [Ca2+]i rises by muscarinic agonist, and transfection of wild-type IRBIT decreased Ca2+i signals, whereas dominant negative IRBIT-S68A had little effect on B2 or P2Y responses but greatly increased muscarinic responses. We conclude that overlaid on microdomain organization is IRBIT, setting a "threshold" for [IP3], assisting in fidelity of receptor specificity.

Original languageEnglish (US)
Pages (from-to)830-841
Number of pages12
JournalJournal of Biological Chemistry
Issue number1
StatePublished - Jan 7 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology


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