Cardiac Gsa overexpression enhances L-type calcium channelsthrough an adenylyl cyclase independent pathway

ALAN S. LADER, YONG-FU XIAO, YOSHIHIRO ISHIKAWA, YANNING CUI, DOROTHY E. VATNER, STEPHEN F. VATNER, CHARLES J. HOMCY AND HORACIO F. CANTIELLO

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Año: 1998 p. 9669 - 9674

0027-8424

The a subunit of the stimulatory heterotrimeric G protein (Gsa) is critical for the b-adrenergic receptor activation of the cAMP messenger system. The role of Gsa in regulating cardiac Ca21 channel activity, however, remains controversial. Cultured neonatal cardiac myocytes from transgenic mice overexpressing cardiac Gsa were used to assess the role of Gsa on the whole-cell Ca21 currents (ICa). Cardiac myocytes from transgenic mice had a 490% higher peak ICa compared with those of either wild-type controls or Gsa-nonexpressing littermates. The effect of Gsa overexpression was mimicked by intracellular dialysis of wild-type cardiac myocytes with GTPgS-activated Gsa. This effect was not mediated by protein kinase A activation as intracellular perfusion with a protein kinase A inhibitor rendered the same degree of activation in either transgenic or wild-type myocytes also dialyzed with activated Gsa. The data indicate that Gsa overexpression is associated with a constitutive enhancement of ICa which is independent of the cAMP pathway and activation of endogenous adenylyl cyclase.a subunit of the stimulatory heterotrimeric G protein (Gsa) is critical for the b-adrenergic receptor activation of the cAMP messenger system. The role of Gsa in regulating cardiac Ca21 channel activity, however, remains controversial. Cultured neonatal cardiac myocytes from transgenic mice overexpressing cardiac Gsa were used to assess the role of Gsa on the whole-cell Ca21 currents (ICa). Cardiac myocytes from transgenic mice had a 490% higher peak ICa compared with those of either wild-type controls or Gsa-nonexpressing littermates. The effect of Gsa overexpression was mimicked by intracellular dialysis of wild-type cardiac myocytes with GTPgS-activated Gsa. This effect was not mediated by protein kinase A activation as intracellular perfusion with a protein kinase A inhibitor rendered the same degree of activation in either transgenic or wild-type myocytes also dialyzed with activated Gsa. The data indicate that Gsa overexpression is associated with a constitutive enhancement of ICa which is independent of the cAMP pathway and activation of endogenous adenylyl cyclase.