A new mode of Ca2+ signaling by G protein-coupled receptors: Gating of IP3 receptor Ca2+ release channels by Gβγ

Weizhong Zeng, Don On Daniel Mak, Qin Li, Dong Min Shin, J. Kevin Foskett, Shmuel Muallem

Research output: Contribution to journalArticlepeer-review

77 Citations (Scopus)


The most common form of Ca2+ signaling by Gq-coupled receptors entails activation of PLCβ2 by Gαq to generate IP3 and evoke Ca2+ release from the ER [1]. Another form of Ca2+ signaling by G protein-coupled receptors involves activation of Gi to release Gβγ, which activates PLCβ1 [2]. Whether Gβγ has additional roles in Ca2+ signaling is unknown. Introduction of Gβγ, into cells activated Ca2+ release from the IP3 Ca2+ pool and Ca2 oscillations [3, 4]. This can be due to activation of PLCβ1 or direct activation of the IP3R by Gβγ. We report here that Gβγ potently activates the IP3 receptor. Thus, Gβγ-triggered [Ca2+]i oscillations are not affected by inhibition of PLCβ. Coimmunoprecipitation and competition experiments with Gβγ scavengers suggest binding of Gβγ to IP3 receptors. Furthermore, Gβγ inhibited IP3 binding to IP3 receptors. Notably, Gβγ activated single IP3R channels in native ER as effectively as IP3. The physiological significance of this form of signaling is demonstrated by the reciprocal sensitivity of Ca2+ signals evoked by Gi- and Gq-coupled receptors to Gβγ scavenging and PLCβ inhibition. We propose that gating of IP3R by Gβγ is a new mode of Ca2+ signaling with particular significance for Gi-coupled receptors.

Original languageEnglish
Pages (from-to)872-876
Number of pages5
JournalCurrent Biology
Issue number10
Publication statusPublished - 2003 May 13

Bibliographical note

Funding Information:
We thank Drs. Elliott Ross, Paul Sternweis, Al Gilman, and Robert Lefkowitz for providing essential probes. We also thank Nataliya Petrenko for assistance with nuclear patch-clamp electrophysiology. This work was supported by the National Institutes of Health.

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Neuroscience(all)


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