TY - JOUR
T1 - On the physiological roles of PIP2 at cardiac Na+- Ca2+ exchangers and KATP channels
T2 - A long journey from membrane biophysics into cell biology
AU - Hilgemann, Donald W.
PY - 2007/8/1
Y1 - 2007/8/1
N2 - Over the last 10 years we have tried to understand the roles of PIP2 in regulating cardiac Na+-Ca+ exchangers and KATP K+ channels, both of which are directly activated by PIP2. Up to now, the idea that hormones might physiologically regulate these mechanisms by causing changes of PIP2 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+ activated and dependent on cardiac activity. Potentially therefore the primary second messenger of the heart, cytoplasmic Ca+, may regulate PIP2 and therewith numerous cardiac membrane processes. In general, however, PIP2 may simply serve to strongly activate various cardiac channels and transporters when they are inserted in the sarcolemma, while a lack of PIP2 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 PIP2 can apparently be countered by strong inactivation mechanisms. In this context, our recent work suggests that internalization of cardiac Na+-Ca+ exchangers is promoted by increased PIP2 synthesis, especially in combination with other cell signals. Assuming that multiple adapter-PIP2 interactions are necessary to initiate the budding of individual membrane vesicles, the dependence of endocytosis on PIP2 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.
AB - Over the last 10 years we have tried to understand the roles of PIP2 in regulating cardiac Na+-Ca+ exchangers and KATP K+ channels, both of which are directly activated by PIP2. Up to now, the idea that hormones might physiologically regulate these mechanisms by causing changes of PIP2 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+ activated and dependent on cardiac activity. Potentially therefore the primary second messenger of the heart, cytoplasmic Ca+, may regulate PIP2 and therewith numerous cardiac membrane processes. In general, however, PIP2 may simply serve to strongly activate various cardiac channels and transporters when they are inserted in the sarcolemma, while a lack of PIP2 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 PIP2 can apparently be countered by strong inactivation mechanisms. In this context, our recent work suggests that internalization of cardiac Na+-Ca+ exchangers is promoted by increased PIP2 synthesis, especially in combination with other cell signals. Assuming that multiple adapter-PIP2 interactions are necessary to initiate the budding of individual membrane vesicles, the dependence of endocytosis on PIP2 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.
UR - http://www.scopus.com/inward/record.url?scp=34547110529&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547110529&partnerID=8YFLogxK
U2 - 10.1113/jphysiol.2007.132746
DO - 10.1113/jphysiol.2007.132746
M3 - Article
C2 - 17463041
AN - SCOPUS:34547110529
SN - 0022-3751
VL - 582
SP - 903
EP - 909
JO - Journal of Physiology
JF - Journal of Physiology
IS - 3
ER -