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

Background-A C825T polymorphism was recently identified in the human gene encoding for the beta(3)-subunit of heterotrimeric G proteins. The 825T allele is associated with a splice variant of GP, and enhanced signal transduction. Pie hypothesized that patients carrying the 825T allele exhibit the modified G beta(3) phenotype. The resulting enhancement of signal transduction should be detectable in the G beta gamma-dimer-mediated acetylcholine-stimulated K+ current (I-K,I-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-KI, I-K,I-ACh) were studied with the whole-cell patch-clamp technique. Background current I-KI 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 mu mol/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 7- 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 G beta(3) 825T allele and amplitude of human atrial I-KI and I-K,I-ACh. Increased background current density in TT carriers could shorten action potential duration and may be due to I-K,I-ACh being constitutively active in this genotype.