PIP₂: A critical regulator of vascular ion channels hiding in plain sight

The phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP₂), has long been established as a major contributor to intracellular signaling, primarily by virtue of its role as a substrate for phospholipase C (PLC). Signaling by G_q-protein-coupled receptors triggers PLC-mediated hydrolysis of PIP₂ into inositol 1,4,5-trisphosphate and diacylglycerol, which are well known to modulate vascular ion channel activity. Often overlooked, however, is the role PIP₂ itself plays in this regulation. Although numerous reports have demonstrated that PIP₂ is critical for ion channel regulation, how it impacts vascular function has received scant attention. In this review, we focus on PIP₂ as a regulator of ion channels in smooth muscle cells and endothelial cells-the two major classes of vascular cells. We further address the concerted effects of such regulation on vascular function and blood flow control. We close with a consideration of current knowledge regarding disruption of PIP₂ regulation of vascular ion channels in disease.