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 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.