Mechanisms of capacitative calcium entry

Capacitative Ca2+ entry involves the regulation of plasma membrane Ca2+ cha nnels by the filling state of intracellular Ca2+ stores in the endoplasmic reticulum (ER). Several theories have been advanced regarding the mechanism by which the stores communicate with the plasma membrane. One such mechani sm, supported by recent findings, is conformational coupling: inositol 1,4, 5-trisphosphate (Ins(1 4,5)P-3) receptors in the ER may sense the fall in C a2+ levels through Ca2+-binding sites on their lumenal domains, and convey this conformational information directly by physically interacting with Ca2 + channels in the plasma membrane. In support of this idea, in some cell ty pes, store-operated channels in excised membrane patches appear to depend o n the presence of both Ins(1,4,5)P3 and Ins(1,4,5)P-3 receptors for activit y; in addition, inhibitors of Ins(1,4,5)P-3 production that either block ph ospholipase C or inhibit phosphatidylinositol 4-kinase can block capacitati ve Ca2+ entry. However, the electrophysiological current underlying capacit ative Ca2+ entry is not blocked by an Ins(1,4,5)P-3 receptor antagonist, an d the blocking effects of a phospholipase C inhibitor are not reversed by t he intracellular application of Ins(1,4,5)P-3. Furthermore, cells whose Ins (1,4,5)P-3 receptor genes have been disrupted can nevertheless maintain the ir capability to activate capacitative Ca2+ entry channels in response to s tore depletion. A tentative conclusion is that multiple mechanisms for sign aling capacitative Ca2+ entry may exist, and involve conformational couplin g in some cell types and perhaps a diffusible signal in others.