Dual regulation of voltage-gated calcium channels by phosphatidylinositol 4,5-biphosphate

Voltage-gated Ca channels (VGCCs) are found in all excitable cells. They mediate Ca2+ influx upon membrane depolarization, initiating many intracellular events such as contraction, secretion, synaptic transmission and gene expression. Owing to their functional significance, the activity of VGCCs is constantly regulated by various signaling pathways in cells. Here we show that VGCCs are regulated bidirectionally by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂). On the one hand, PI(4,5)P₂ activates and stabilizes the VGCCs in inside-out patches as well as in intact cells. Increasing the membrane PI(4,5)P₂ level by adding PI(4,5)P₂ liposomes or MgATP into the intracellular medium stabilizes channel activity and prevents channel rundown. Conversely, lowering the membrane PI(4,5)P₂ level with anti-PI(4,5)P₂ antibodies or PI(4,5)P₂-binding peptides or via receptor-triggered hydrolysis results in channel rundown or inhibition. The latter mechanism may underlie a G proteins-induced, voltage-independent inhibitory pathway known as “sman”. On the other hand, PI(4,5)P ₂ inhibits VGCCs by shifting the voltage dependence of channel activation toward more positive potentials and making the channel harder to open. PKA phosphorylation prevents and even reverses this inhibition, thereby facilitating channel activation. Presumably, PI(4,5)P₂ binds to two distinct domains on VGCCs to produce these effects. The dual actions of PI(4,5)P₂ thus sets up a pivotal regulatory mechanism through which the activity of VGCCs can be finely tuned by numerous neurotransmitters, hormones and neurotrophic factors.