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Am J Physiol Cell Physiol (October 20, 2004). doi:10.1152/ajpcell.00124.2004
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Submitted on March 5, 2004
Accepted on October 19, 2004

{alpha}1-Adrenoceptors stimulate a G{alpha}s protein and reduce the transient outward K+ current via a cAMP/PKA-mediated pathway in the rat heart

Monica Gallego1, Raul Setien2, Lilian Puebla3, Maria del Carmen Boyano-Adanez3, Eduardo Arilla3, and Oscar Casis1*

1 Department of Physiology, Universidad del Pais Vasco, Bilbao, Vizcaya, Spain
2 Department of Physiology, Universidad del Pais Vasco, Bilbao, Vizcaya, Spain; Department of Biochemistry and Molecular Biology, Universidad de Alcala, Alcala de Henares, Madrid, Spain
3 Department of Biochemistry and Molecular Biology, Universidad de Alcala, Alcala de Henares, Madrid, Spain

* To whom correspondence should be addressed. E-mail: ofpcasao{at}lg.ehu.es.

{alpha}1-adrenoceptor stimulation prolongs the duration of the cardiac action potential and leads to positive inotropic effect by inhibiting the transient outward potassium current (Ito). Here, we have examined the role of several protein kinases and the G protein involved in Ito inhibition in response to {alpha}1-adrenoceptor stimulation in isolated adult rat ventricular myocytes. Our findings exclude the classical {alpha}1-adrenergic pathway: activation of the G protein G{alpha}q, phospholipase C (PLC) and protein kinase C (PKC), because neither PLC, PKC nor G{alpha}q blockade prevent the {alpha}1-induced Ito reduction. On the contrary, the {alpha}1-adrenoceptor does not inhibit Ito in the presence of PKA, adenylyl cyclase or G{alpha}s inhibitors. In addition, PKA and adenylyl cyclase activation inhibit Ito to the same extent as phenylephrine. Finally, we show a functional coupling between the {alpha}1-adrenoceptor and G{alpha}s in a physiological system. Moreover, this coupling seems to be compartmentalized since the {alpha}1-adrenoceptor increases cAMP levels only in intact cells, but not in isolated membranes, and the effect on Ito current disappears when the cytoskeleton is disrupted. We conclude that {alpha}1-adrenoceptor stimulation reduces the amplitude of the Ito current by activating a G{alpha}s protein and the cAMP/PKA signaling cascade, which in turn leads to Ito channel phosphorylation.




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