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Volume 272, Number 12, Issue of March 21, 1997 pp. 7770-7776
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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5-HT_1A Receptor Activates Na⁺/H⁺ Exchange in CHO-K1 Cells through G_i2 and G_i3

(Received for publication, September 19, 1996, and in revised form, December 12, 1996)

Maria N. Garnovskaya ^‡ , Thomas W. Gettys ^‡§ , Tim van Biesen ^¶ , Veronica Prpic ^‡ , J. Kurt Chuprun ^¶ and John R. Raymond ^‡

From the Departments of ^‡ Medicine and ^§ Biochemistry and Molecular Biology, Medical University of South Carolina and Veterans Affairs Medical Centers, Charleston, South Carolina 29425 and the ^¶ Department of Medicine, Duke University Medical Center and  Howard Hughes Medical Institute, Durham, North Carolina 27710

5-HT_1A receptors couple to many signaling pathways in CHO-K1 cells through pertussis toxin-sensitive G proteins. The purpose of this study was to determine which members of the G_i/o/z family mediate 5-HT_1A receptor-activated Na⁺/H⁺ exchange as measured by microphysiometry of cell monolayers. The method was extensively validated, showing that proton efflux was sodium-dependent, inhibited by amiloride analogs, and activated by growth factors, phorbol ester, calcium ionophore, and hypertonic stress. 5-HT and the specific agonist (±)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide rapidly stimulated proton efflux that was blocked by a specific receptor antagonist, amiloride analogs or pertussis toxin. The activation by 5-HT depended upon extracellular sodium and could be demonstrated under conditions of imposed intracellular acid load, as well as in the presence and absence of glycolytic substrate. Acceleration of proton efflux was not inhibited by sequestration of G protein -subunits, a maneuver that blocked 5-HT_1A receptor activation of mitogen-activated protein kinase. Transfection of G_z and pertussis toxin-resistant mutants of G_o and G_i1 did not reverse the blockade induced by pertussis toxin. In contrast, pertussis toxin-resistant mutants of G_i2 and G_i3 "rescued" the ability of 5-HT to increase proton efflux after pertussis toxin treatment. These experiments demonstrate clearly that G_i2 and G_i3 can specifically mediate rapid agonist-induced acceleration of Na⁺/H⁺ exchange.

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