Regulation of Ca2+ entry pathways by both limbs of the phosphoinositide pathway.

All inositol 1,4,5-trisphosphate (InsP3) receptors are biphasically regulated by cytosolic Ca2+. For type 2 InsP3 receptors, InsP3 binding controls whether a stimulatory Ca2+-binding site (exposed after InsP3 binding) or an inhibitory Ca2+-binding site (exposed only in the absence of InsP3) is accessible. Ca2+ therefore inhibits these InsP3 receptors only after InsP3 has dissociated. The capacitative Ca2+ entry (CCE) pathway is activated by depletion of Ca2+ stores, but the local increase in cytosolic [Ca2+] as Ca2+ flows through these channels could cause long-lasting inhibition of InsP3 receptors and so termination of the signal that activates CCE. However, the duration of the openings of CCE channels is matched to the behaviour of InsP3 receptors such that during the brief openings of CCE channels, active InsP3 receptors are unlikely to lose enough InsP3 for them to become inhibited. In A7r5 vascular smooth muscle cells, CCE and a non-capacitative Ca2+ entry (NCCE) pathway, which is activated by arachidonic acid released from diacylglycerol by diacylglycerol lipase, can be distinguished by their different permeation properties and sensitivity to selective blockers. Arachidonic acid also inhibits CCE and so ensures that during receptor activation only the NCCE pathway mediates Ca2+ entry, while CCE contributes only after removal of the agonist.