Receptor Species-dependent Desensitization Controls KCNQ1/KCNE1 K+ Channels as Downstream Effectors of Gq Protein-coupled Receptors.

Activation of G protein-coupled receptors (GPCRs) might induce divergent cellular responses, related to receptor-specific activation of different branches of the G signaling pathway. Receptor-specific desensitization provides a mechanism of effector modulation by restricting the spatiotemporal activation of signaling components downstream of G We quantified signaling events downstream of GPCR activation with FRET-based biosensors in CHO and HEK 293 cells. KCNQ1/KCNE1 channels (I) were measured as a functional readout of receptor-specific activation. Activation of muscarinic M receptors (M-Rs) caused robust and reversible inhibition of I In contrast, activation of α-adrenergic receptors (α-ARs) induced transient inhibition of I, which turned into delayed facilitation after agonist withdrawal. As a novel finding, we demonstrate that GPCR-specific kinetics of I modulation are determined by receptor-specific desensitization, evident at the level of Gα activation, phosphatidylinositol 4,5-bisphosphate (PIP) depletion, and diacylglycerol production. Sustained I inhibition during M-R stimulation is attributed to robust membrane PIP depletion, whereas the rapid desensitization of α-AR delimits PIP reduction and augments current activation by protein kinase C (PKC). Overexpression of Ca-independent PKCδ did not affect the time course of α-AR-induced diacylglycerol formation, excluding a contribution of PKCδ to α-AR desensitization. Pharmacological inhibition of Ca-dependent PKC isoforms abolished fast α receptor desensitization and augmented I reduction, but did not affect I facilitation. These data indicate a contribution of Ca-dependent PKCs to α-AR desensitization, whereas I facilitation is induced by Ca-independent PKC isoforms. In contrast, neither inhibition of Ca-dependent/Ca-independent isoforms nor overexpression of PKCδ induced M receptor desensitization, excluding a contribution of PKC to M-R-induced I modulation.