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J Biol Chem, Vol. 275, Issue 3, 2087-2097, January 21, 2000

Constitutively Active Mutants of the alpha 1a- and the alpha 1b-Adrenergic Receptor Subtypes Reveal Coupling to Different Signaling Pathways and Physiological Responses in Rat Cardiac Myocytes*

Charlene McWhinneyDagger §, Dean WenhamDagger , Sujata Kanwal, Vivian Kalman, Carl Hansen, and Janet D. Robishaw

From the Henry Hood Research Program, Pennsylvania State College of Medicine, Danville, Pennsylvania 17822-2614 and § Oklahoma State University, School of Medicine, Department of Physiology and Pharmacology, Tulsa, Oklahoma 74107

Activation of alpha 1-adrenergic receptors influences both the contractile activity and the growth potential of cardiac myocytes. However, the signaling pathways linking activation of specific alpha 1-adrenergic receptor (AR) subtypes to these physiological responses remain controversial. In the present study, a molecular approach was used to identify conclusively the signaling pathways activated in response to the individual alpha 1A- and alpha 1B-AR subtypes in cardiac myocytes. For this purpose, a mutant alpha 1a-AR subtype (alpha 1a-S290/293-AR) was constructed based on analogy to the previously described constitutively active mutant alpha 1b-AR subtype (alpha 1b-S288-294-AR). The mutant alpha 1a-S290/293-AR subtype displayed constitutive activity based on four criteria. To introduce the constitutively active alpha 1-AR subtypes into cardiac myocytes, recombinant Sindbis viruses encoding either the alpha 1a-S290/293-AR or alpha 1b-S288-294-AR subtype were used to infect the whole cell population with >90% efficiency, thereby allowing the biochemical activities of the various signaling pathways to be measured. When expressed at comparable levels, the alpha 1a-S290/293-AR subtype exhibited a significantly elevated basal level as well as agonist-stimulated level of inositol phosphate accumulation, coincident with activation of atrial natriuretic factor-luciferase gene expression. By contrast, the alpha 1b-S288-294-AR subtype displayed a markedly increased serum response element-luciferase gene expression but no activation of atrial natriuretic factor-luciferase gene expression. Taken together, this study provides the first molecular evidence for coupling of the alpha 1a-AR and the alpha 1b-AR subtypes to different signaling pathways in cardiac myocytes.

* This research was supported by National Institutes of Health Grants HL 49278 (to J. D. R.) and DK 45417 (to C. A. H.).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.

Dagger Both authors contributed equally to this work and should be considered as joint first authors.

To whom correspondence should be addressed: Henry Hood Research Program, Pennsylvania State College of Medicine, Weis Center for Research, 100 North Academy Ave., Danville, PA 17822. Tel.: 570-271-6684; Fax: 570-271-6701.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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