Tyrosine kinase and protein kinase C regulate L-type Ca(2+) current cooperatively in human atrial myocytes.
The effects of tyrosine protein kinases (TK) on the L-type Ca(2+) current (I(Ca)) were examined in whole cell patch-clamped human atrial myocytes. The TK inhibitors genistein (50 microM), lavendustin A (50 microM), and tyrphostin 23 (50 microM) stimulated I(Ca) by 132 +/- 18% (P < 0.001), 116 +/- 18% (P < 0.05), and 60 +/- 6% (P < 0.001), respectively. After I(Ca) stimulation by genistein, external application of isoproterenol (1 microM) caused an additional increase in I(Ca). Dialyzing the cells with a protein kinase A inhibitor suppressed the effect of isoproterenol on I(Ca) but not that of genistein. Inhibition of protein kinase C (PKC) by pretreatment of cells with 100 nM staurosporine or 100 nM calphostin C prevented the effects of genistein on I(Ca). The PKC activator phorbol 12-myristate 13-acetate (PMA), after an initial stimulation (75 +/- 17%, P < 0.05), decreased I(Ca) (-36 +/- 5%, P < 0.001). Once the inhibitory effect of PMA on I(Ca) had stabilized, genistein strongly stimulated the current (323 +/- 25%, P < 0.05). Pretreating myocytes with genistein reduced the inhibitory effect of PMA on I(Ca). We conclude that, in human atrial myocytes, TK inhibit I(Ca) via a mechanism that involves PKC.
Boixel
C
C
Institut National de la Santé et de la Recherche Médicale, Unité 460, Faculté de Médecine Xavier Bichat, Paris, France.
Tessier
S
S
Pansard
Y
Y
Lang-Lazdunski
L
L
Mercadier
J J
JJ
Hatem
S N
SN
D000293:Adolescent; D000328:Adult; D000368:Aged; D020746:Calcium Channels, L-Type / Q000502:physiology*; D004553:Electric Conductivity; D006325:Heart Atria; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*
D020746:Calcium Channels, L-Type; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C