A novel mechanism for the store-operated calcium influx pathway.
Activation of store-operated channels (SOCs) and capacitative calcium influx are triggered by depletion of intracellular calcium stores. However, the exact molecular mechanism of such communication remains unclear. Recently, we demonstrated that native SOC channels can be activated by calcium influx factor (CIF) that is produced upon depletion of calcium stores, and showed that Ca(2+)-independent phospholipase A(2) (iPLA(2)) has an important role in the store-operated calcium influx pathway. Here, we identify the key plasma-membrane-delimited events that result in activation of SOC channels. We also propose a novel molecular mechanism in which CIF displaces inhibitory calmodulin (CaM) from iPLA(2), resulting in activation of iPLA(2) and generation of lysophospholipids that in turn activate soc channels and capacitative calcium influx. Upon refilling of the stores and termination of CIF production, CaM rebinds to iPLA(2), inhibits it, and the activity of SOC channels and capacitative calcium influx is terminated.
Smani
Tarik
T
Boston University School of Medicine, Boston, MA 02118, USA.
Zakharov
Sergey I
SI
Csutora
Peter
P
Leno
Endri
E
Trepakova
Elena S
ES
Bolotina
Victoria M
VM
D000818:Animals; D001685:Biological Factors; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010741:Phospholipases A / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology; D019284:Thapsigargin / Q000378:metabolism
D001685:Biological Factors; D015220:Calcium Channels; D002147:Calmodulin; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008246:Lysophospholipids; C031938:calmidazolium; D019284:Thapsigargin; D010741:Phospholipases A; D002118:Calcium