G-Protein β 3 -Subunit 825T Allele Is Associated With Enhanced Human Atrial Inward Rectifier Potassium Currents

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Abstract
Background —A C825T polymorphism was recently identified in the human gene encoding for the β 3 -subunit of heterotrimeric G proteins. The 825T allele is associated with a splice variant of Gβ 3 and enhanced signal transduction. We hypothesized that patients carrying the 825T allele exhibit the modified Gβ 3 phenotype. The resulting enhancement of signal transduction should be detectable in the Gβγ-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 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 Conclusions —We found an association between the Gβ 3 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.