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Intracellular Fragments of the Natriuretic Peptide Receptor-C (NPR-C) Attenuate Dopamine Efflux¹

Department of Biochemistry (S.K.), Vanderbilt University Medical School, Nashville, Tennessee 37212; Cardiovascular Research Department (D.G.L.), Genentech, Inc., South San Francisco, California 94080; and Department of Pharmacology (G.J.T.), University of Minnesota-Duluth, School of Medicine, Duluth, Minnesota 55812

Address all correspondence and requests for reprints to: George J. Trachte, Department of Pharmacology, University of Minnesota-Duluth, School of Medicine, 10 University Drive, Duluth, Minnesota 55812. E-mail: gtracht1{at}d.umn.edu

Natriuretic peptides suppress adrenergic neurotransmission by a mechanism apparently involving the natriuretic peptide receptor-C (NPR-C) rather than particulate guanylyl cyclase receptors. The bulk of evidence implicating the NPR-C in neuromodulatory effects relies on the pharmacological specificity of peptides believed to be specific for the NPR-C. This study tests for NPR-C effects on neurotransmitter release by examining fragments of the receptor for biological activity in pheochromocytoma (PC12) cells permeabilized with digitonin. A pentadecapeptide segment of the cytoplasmic portion of the NPR-C mimicked the effect of natriuretic peptides to suppress dopamine efflux evoked by calcium approximately 40%. Furthermore, an antibody generated against the pentadecapeptide fragment abolished the neuromodulatory effect of C-type natriuretic peptide in permeabilized cells. In contrast, the carboxy terminal nonadecapeptide portion of the NPR-C failed to attenuate dopamine efflux. These data are consistent with the proposed role of the NPR-C in transducing the biological activity of natriuretic peptides in adrenergic tissue. The most novel aspect of these observations involves the potency of the small cytosolic region of the NPR-C with the region closest to the membrane accounting for neuromodulatory effects.

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