The lipid connection-regulation of voltage-gated Ca2+ channels by phosphoinositides

Recent findings have revealed a pivotal role for phospholipids phosphatidylinositol -4,5-biphosphate (PIP2) and phosphatidylinositol -3,4,5-trisphosphate (PIP3) in the regulation of high voltage-activated (HVA) Ca2+ channels. PIP2 exerts two opposing actions on HVA Ca2+ channels: It stabilizes their activity but also produces a voltage-dependent inhibition that can be antagonized by protein kinase A (PKA) phosphorylation. PIP2 depletion and arachidonic acid together mediate the slow, voltage-independent inhibition of HVA Ca2+ channels by G (q/11) -coupled receptors in neurons. A sufficient level of plasma membrane PIP2 also appears to be necessary for G (beta gamma) -mediated inhibition. On the other hand, increased production of PIP3 by PI-3 kinases promotes trafficking of HVA Ca2+ channels to the plasma membrane. This review discusses these findings and their implications.