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(Circulation. 2000;102:692.)
© 2000 American Heart Association, Inc.

Basic Science Reports

G-Protein ß₃-Subunit 825T Allele Is Associated With Enhanced Human Atrial Inward Rectifier Potassium Currents

D. Dobrev, MD; E. Wettwer, PhD; H. M. Himmel, MD; A. Kortner, MD; E. Kuhlisch, DM; S. Schüler, MD, PhD; W. Siffert, MD, PhD; U. Ravens, MD, PhD

From the Department of Pharmacology and Toxicology (D.D., E.W., H.M.H., U.R.), Cardiovascular Centre Dresden (A.K., S.S.), and Department of Medical Informatics and Biometry (E.K.), Medical Faculty, University of Technology, Dresden; and the Department of Pharmacology, Medical Faculty, Essen University, Essen (W.S.), Germany.

Correspondence to Prof Dr med Ursula Ravens, Institut für Pharmakologie und Toxikologie, Karl-Marx-Straße 3, D-01109 Dresden, Germany. E-mail ravens{at}rcs.urz.tu-dresden.de

Background—A C825T polymorphism was recently identified in the human gene encoding for the ß₃-subunit of heterotrimeric G proteins. The 825T allele is associated with a splice variant of Gß₃ and enhanced signal transduction. We hypothesized that patients carrying the 825T allele exhibit the modified Gß₃ phenotype. The resulting enhancement of signal transduction should be detectable in the Gß-dimer–mediated acetylcholine-stimulated K⁺ current (I_K,ACh).

Methods and Results—Seventy patients undergoing cardiac surgery were genotyped for the C825T polymorphism. In right atrial myocytes from these patients, the inward rectifier K⁺ currents (I_K1, I_K,ACh) were studied with the whole-cell patch-clamp technique. Background current I_K1 was measured with depolarizing ramp pulses and quantified as inward current at -100 mV; mean amplitudes were (pA/pF) 4.98±0.49 (n=30/93 patients/cells) in patients with CC genotype, 4.25±0.36 (n=31/121 patients/cells) with TC, and 7.46±1.14 (n=9/32 patients/cells; P<0.05) with TT. Conversely, mean I_K,ACh, which is maximally activated by carbachol (2 µmol/L), was reduced in patients with TT genotype (pA/pF, 4.30±1.33, n=9/27 patients/cells; P<0.05) compared with the other 2 groups (6.56±0.54, n=30/80 and 6.16±0.45, n=31/117 patients/cells, for CC and TC genotype, respectively). Essentially similar results were obtained with adenosine (1 mmol/L).

Conclusions—We found an association between the Gß₃ 825T allele and amplitude of human atrial I_K1 and I_K,ACh. Increased background current density in TT carriers could shorten action potential duration and may be due to I_K,ACh being constitutively active in this genotype.

Key Words: myocytes • ions • genes • carbachol • adenosine

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