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(V)1.2 and Ca(V)1.3 channel currents by similar to 35% and Ca(V)2.1 and Ca(V)2.2 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(V)2.2 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.