G-protein β3-subunit 825T allele is associated with enhanced human atrial inward rectifier potassium currents

Abstract

Background - A C825T polymorphism was recently identified in the human gene encoding for the β3-subunit of heterotrimeric G proteins. The 825T allele is associated with a splice variant of Gβ3 and enhanced signal transduction. We hypothesized that patients carrying the 825T allele exhibit the modified Gβ3 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<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 Gβ3 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.