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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

₁-Adrenoceptors stimulate a G_s protein and reduce the transient outward K⁺ current via a cAMP/PKA-mediated pathway in the rat heart

¹Department of Physiology, School of Pharmacy, Universidad del País Vasco, Bilbao; and ²Department of Biochemistry and Molecular Biology, School of Medicine, Universidad de Alcalá, Alcalá de Henares, Spain

Submitted 5 March 2004 ; accepted in final form 19 October 2004

₁-Adrenoceptor stimulation prolongs the duration of the cardiac action potentials and leads to positive inotropic effects by inhibiting the transient outward K⁺ current (I_to). In the present study, we have examined the role of several protein kinases and the G protein involved in I_to inhibition in response to ₁-adrenoceptor stimulation in isolated adult rat ventricular myocytes. Our findings exclude the classic ₁-adrenergic pathway: activation of the G protein G_q, phospholipase C (PLC), and protein kinase C (PKC), because neither PLC, nor PKC, nor G_q blockade prevents the ₁-induced I_to reduction. To the contrary, the ₁-adrenoceptor does not inhibit I_to in the presence of protein kinase A (PKA), adenylyl cyclase, or G_s inhibitors. In addition, PKA and adenylyl cyclase activation inhibit I_to to the same extent as phenylephrine. Finally, we have shown a functional coupling between the ₁-adrenoceptor and G_s in a physiological system. Moreover, this coupling seems to be compartmentalized, because the ₁-adrenoceptor increases cAMP levels only in intact cells, but not in isolated membranes, and the effect on I_to disappears when the cytoskeleton is disrupted. We conclude that ₁-adrenoceptor stimulation reduces the amplitude of the I_to by activating a G_s protein and the cAMP/PKA signaling cascade, which in turn leads to I_to channel phosphorylation.

potassium currents; compartmentalization

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