TY - JOUR T1 - Phosphotidylinositol 4,5-Bisphosphate Signals Underlie Receptor-Specific G<sub>q/11</sub>-Mediated Modulation of N-Type Ca<sup>2+</sup> Channels JF - The Journal of Neuroscience JO - J. Neurosci. SP - 10980 LP - 10992 DO - 10.1523/JNEUROSCI.3869-04.2004 VL - 24 IS - 48 AU - Nikita Gamper AU - Vitaliy Reznikov AU - Yoichi Yamada AU - Jian Yang AU - Mark S. Shapiro Y1 - 2004/12/01 UR - http://www.jneurosci.org/content/24/48/10980.abstract N2 - 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, PIP2 greatly attenuated or reversed the observed rundown of expressed channels. In sympathetic neurons, muscarinic M1 ACh receptor suppression of the Ca2+ current (ICa) was temporally correlated with PIP2 hydrolysis, blunted by PIP2 in whole-cell pipettes, attenuated by expression of PIP2-sequestering proteins, and became irreversible when PIP2 synthesis was blocked. We also probed mechanisms of receptor specificity. Although bradykinin also induced PIP2 hydrolysis, it did not inhibit ICa. However, bradykinin receptors became nearly as effective as M1 receptors when PIP2 synthesis, IP3 receptors, or the activity of neuronal Ca2+ sensor-1 were blocked, suggesting that bradykinin receptor-induced intracellular Ca2+ increases stimulate PIP2 synthesis, compensating for PIP2 hydrolysis. We suggest that differential use of PIP2 signals underlies specificity of Gq/11-coupled receptor actions on the channels. ER -