Inhibition of L-type calcium current by genistein, a tyrosine kinase inhibitor, in pregnant rat myometrial cells.
Possible regulation of L-type Ca2+ channels by tyrosine kinase was examined in freshly isolated uterine smooth muscle cells obtained from late pregnant (18-19 day) rat, using whole-cell voltage clamp. Bath application of genistein, an inhibitor of tyrosine kinase, decreased L-type Ca2+ current (ICa(L)) dose-dependently. The maximal inhibition of ICa(L) was 46% and the concentration for half-maximal inhibition (IC50) was 50 microM (at a holding potential of -60 mV). The effect of genistein was reversible. Daidzein, an inactive analog of genistein, had no inhibitory effect on ICa(L) at concentrations as high as 300 microM. The steady-state inactivation curve for ICa(L) was shifted to the left by genistein (15 mV at 100 microM), whereas the activation curve was not affected, suggesting that genistein exerts.a voltage-dependent block. These results suggest that the L-type Ca2+ channels in myometrial cells may be modulated by endogenous tyrosine kinase, i.e., they are in a tonically stimulated state due to tyrosine kinase activity. This modulatory mechanism may play a role on the regulation of Ca2+ influx and uterine contraction during normal labor and preterm labor.
Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, OH 45267-0576, USA.
M
M
Kusaka
N
N
Sperelakis
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015220:Calcium Channels; D007529:Isoflavones; D019833:Genistein; D011505:Protein-Tyrosine Kinases