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(Circulation Research. 2000;86:643.)
© 2000 American Heart Association, Inc.

Cellular Biology

Overexpressed A₁ Adenosine Receptors Reduce Activation of Acetylcholine-Sensitive K⁺ Current by Native Muscarinic M₂ Receptors in Rat Atrial Myocytes

Marie-Cécile Wellner-Kienitz, Kirsten Bender, Thomas Meyer, Moritz Bünemann, Lutz Pott

From Abteilung Zelluläre Physiologie, Ruhr-Universität Bochum, Bochum, Germany, and the Department of Molecular Pharmacology and Biological Chemistry (M.B.), Northwestern University Medical School, Chicago, Ill.

Correspondence to Dr Lutz Pott, Ruhr-Universität Bochum, Abteilung Zelluläre Physiologie, D-44780 Bochum, Germany. E-mail lutz.pott{at}ruhr-uni-bochum.de

Abstract—In adult rat atrial myocytes, muscarinic acetylcholine (ACh)-sensitive K⁺ current activated by a saturating concentration of adenosine (I_K(ACh),(Ado)) via A₁ receptors (A₁Rs) amounts to only 30% of the current activated by a saturating concentration of ACh (I_K(ACh),(ACh)) via muscarinic M₂ receptors. The half-time of activation of I_K(ACh),(Ado) on a rapid exposure to agonist was 4-fold longer than that of I_K(ACh),(ACh). Furthermore, I_K(ACh),(Ado) never showed fast desensitization. To study the importance of receptor density for A₁R-I_K(ACh),(Ado) signaling, adult atrial myocytes in vitro were transfected with cDNA encoding for rat brain A₁R and enhanced green fluorescent protein (EGFP) as a reporter. Whole-cell current was measured on days 3 and 4 after transfection. Time-matched cells transfected with only the EGFP vector served as controls. In 30% of EGFP-positive cells (group I), the density of I_K(ACh),(Ado) was increased by 72%, and its half-time of activation was reduced. Density and kinetic properties of I_K(ACh),(ACh) were not affected in this fraction. In 70% of transfection-positive myocytes (group II), the density of I_K(ACh),(ACh) was significantly reduced, its activation was slowed, and the fast desensitizing component was lost. Adenosine-induced currents were larger in group II than in group I, their activation rate was further increased, and a fast desensitizing component developed. These data indicate that in native myocytes the amplitude and activation kinetics of I_K(ACh),(Ado) are limited by the expression of A₁R. Overexpression of A₁R negatively interferes with signal transduction via the muscarinic M₂ receptor–linked pathway, which might reflect a competition of receptors with a common pool of G proteins. Negative interference of an overexpressed receptor with physiological regulation of a target protein by a different receptor should be considered in attempts to use receptor overexpression for gene therapy.

Key Words: atrial myocytes • gene transfer • muscarinic receptors • adenosine receptors • K⁺ currents

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