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Originally published In Press as doi:10.1074/jbc.M105572200 on August 27, 2001

J. Biol. Chem., Vol. 276, Issue 44, 40811-40816, November 2, 2001
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Different Subtypes of alpha 1-Adrenoceptor Modulate Different K+ Currents via Different Signaling Pathways in Canine Ventricular Myocytes*

Huizhen WangDagger §, Baofeng Yang||, Yiqiang ZhangDagger , Hong HanDagger **, Jingxiong WangDagger , Hong ShiDagger , and Zhiguo WangDagger Dagger Dagger §§

From the Dagger  Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada, the Dagger Dagger  Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada, and the || Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang 150086, China

Multiple subtypes (alpha 1A, alpha 1B, and alpha 1D) of alpha 1-adrenoreceptors (alpha 1ARs) co-exist in the heart and mediate a variety of cellular functions. We studied alpha 1AR modulation of inward rectifier (IK1) and transient outward (Ito) K+ currents in canine ventricular myocytes. Phenylephrine at 10 µM depressed only Ito without affecting IK1 and at 100 µM inhibited both Ito and IK1. The effect of phenylephrine on Ito was abolished by (+)niguldipine (10 nM) to inhibit alpha 1AARs but not by chloroethyclonidine (10 µM) to inactivate alpha 1BARs nor by BMY-7378 to antagonize alpha 1DARs. In contrast, phenylephrine inhibition of IK1 was reversed only by BMY-7378 (1 nM). PDD (100 nM, phorbol ester activator of protein kinase C (PKC)) simulates and bisindolylmaleimide (50 nM, PKC inhibitor) weakens phenylephrine modulation of Ito but not IK1. Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 and inhibitor peptides abolished the effects of phenylephrine on IK1. Enhancement of PKC or CaMKII activities was seen in alpha 1aAR- or alpha 1dAR-transfected HEK293 cells and in myocytes pretreated with 10 or 100 µM phenylephrine, respectively. Our data suggest that different subtypes of alpha 1ARs selectively modulate different cardiac K+ currents via different signal transduction mechanisms; alpha 1AARs mediate Ito regulation via PKC, and alpha 1DARs mediate IK1 regulation via CaMKII.


* This work was supported in part by funds from the Canadian Institute of Health Research, the Heart and Stroke Foundation of Quebec, and the Fonds de la Recherche de l'Institut de Cardiologie de Montreal (to Z. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Research fellow of the Canadian Institute of Health Research.

These authors contributed equally to this work.

** Research fellow of the Heart and Stroke Foundation of Canada.

§§ Research scholar of the Heart and Stroke Foundation of Canada. To whom correspondence should be addressed: Research Center, Montreal Heart Inst., 5000 Belanger East, Montreal, PQ H1T 1C8, Canada. Tel.: 514-376-3330; Fax: 514-376-1355; E-mail: wangz@icm.umontreal.ca.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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