On the physiological roles of PIP(2) at cardiac Na+ Ca2+ exchangers and K(ATP) channels: a long journey from membrane biophysics into cell biology.
Over the last 10 years we have tried to understand the roles of PIP(2) in regulating cardiac Na(+)-Ca(2+) exchangers and K(ATP) K(+) channels, both of which are directly activated by PIP(2). Up to now, the idea that hormones might physiologically regulate these mechanisms by causing changes of PIP(2) concentrations in the cardiac sarcolemma, either locally or globally, is not well supported. In intact myocardium, but not excised patches, phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity appears to be Ca(2+) activated and dependent on cardiac activity. Potentially therefore the primary second messenger of the heart, cytoplasmic Ca(2+), may regulate PIP(2) and therewith numerous cardiac membrane processes. In general, however, PIP(2) may simply serve to strongly activate various cardiac channels and transporters when they are inserted in the sarcolemma, while a lack of PIP(2) on internal membranes maintains transporters and channels inactive during trafficking and processing. As in most, if not all, strong regulatory systems of cells, the activating effects of PIP(2) can apparently be countered by strong inactivation mechanisms. In this context, our recent work suggests that internalization of cardiac Na(+)-Ca(2+) exchangers is promoted by increased PIP(2) synthesis, especially in combination with other cell signals. Assuming that multiple adapter-PIP(2) interactions are necessary to initiate the budding of individual membrane vesicles, the dependence of endocytosis on PIP(2) in the surface membrane can potentially be a very steep function. Thus, a better understanding of the regulation of cardiac lipid kinases may be key to understanding when and how cardiac ion transporters and channels are internalized.
Hilgemann
Donald W
DW
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA. donald.hilgemann@utsouthwestern.edu
D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D000099161:Kcnj11 Channel
D019269:Phosphatidylinositol 4,5-Diphosphate; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel