Modulation of high-voltage activated Ca²⁺ channels by membrane phosphatidylinositol 4,5-bisphosphate

Modulation of voltage-gated Ca²⁺ channels controls activities of excitable cells. We show that high-voltage activated Ca²⁺ channels are regulated by membrane phosphatidylinositol 4,5-bisphosphate (PIP₂) with different sensitivities. Plasma membrane PIP₂ depletion by rapamycin-induced translocation of an inositol lipid 5-phosphatase or by a voltage-sensitive 5-phosphatase (VSP) suppresses Ca_V1.2 and Ca_V1.3 channel currents by ∼35% and Ca_V2.1 and Ca_V2.2 currents by 29% and 55%, respectively. Other Ca_V channels are less sensitive. Inhibition is not relieved by strong depolarizing prepulses. It changes the voltage dependence of channel gating little. Recovery of currents from inhibition needs intracellular hydrolysable ATP, presumably for PIP₂ resynthesis. When PIP₂ is increased by overexpressing PIP 5-kinase, activation and inactivation of Ca_V2.2 current slow and voltage-dependent gating shifts to slightly higher voltages. Thus, endogenous membrane PIP₂ supports high-voltage activated L-, N-, and P/Q-type Ca²⁺ channels, and stimuli that activate phospholipase C deplete PIP₂ and reduce those Ca²⁺ channel currents.