Phosphotidylinositol 4,5-Bisphosphate Signals Underlie Receptor-Specific Gq/11-Mediated Modulation of N-Type Ca2+Channels

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Abstract
Modulation of voltage-gated Ca2+channels via G-protein-coupled receptors is a prime mechanism regulating neurotransmitter release and synaptic plasticity. Despite extensive studies, the molecular mechanism underlying Gq/11-mediated modulation remains unclear. We found cloned and native N-type Ca2+channels to be regulated by phosphotidylinositol 4,5-bisphosphate (PIP2). In inside-out oocyte patches, PIP2greatly attenuated or reversed the observed rundown of expressed channels. In sympathetic neurons, muscarinic M1ACh receptor suppression of the Ca2+current (ICa) was temporally correlated with PIP2hydrolysis, blunted by PIP2in whole-cell pipettes, attenuated by expression of PIP2-sequestering proteins, and became irreversible when PIP2synthesis was blocked. We also probed mechanisms of receptor specificity. Although bradykinin also induced PIP2hydrolysis, it did not inhibitICa. However, bradykinin receptors became nearly as effective as M1receptors when PIP2synthesis, IP3receptors, or the activity of neuronal Ca2+sensor-1 were blocked, suggesting that bradykinin receptor-induced intracellular Ca2+increases stimulate PIP2synthesis, compensating for PIP2hydrolysis. We suggest that differential use of PIP2signals underlies specificity of Gq/11-coupled receptor actions on the channels.