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

The most common form of Ca2+ signaling by Gq-coupled receptors entails activation of PLCbeta2 by Galphaq 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 Gbetagamma, which activates PLCbeta1 [2]. Whether GOT has additional roles in Ca2+ signaling is unknown. Introduction of Gbetagamma into cells activated Ca2+ release from the IP3 Ca2+ pool and Ca2+ oscillations [3, 4]. This can be due to activation of PLCbeta1 or direct activation of the IP3R by Gbetagamma. We report here that Gbetagamma potently activates the IP3 receptor. Thus, Gbetagamma-triggered [Ca2+](i) oscillations are not affected by inhibition of PLCbeta. Coimmunoprecipitation and competition experiments with Gbetagamma scavengers suggest binding of Gbetagamma to IP3 receptors. Furthermore, Gbetagamma inhibited IP3 binding to IP3 receptors. Notably, Gbetagamma 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 Gbetagamma scavenging and PLCbeta inhibition. We propose that gating of IP3R by Gbetagamma is a new mode of Ca2+ signaling with particular significance for Gi-coupled receptors.