G-protein beta 3-subunit 825T allele is associated with enhanced human atrial inward rectifier potassium currents

Background-A C825T polymorphism was recently identified in the human gene e ncoding for the beta(3)-subunit of heterotrimeric G proteins. The 825T alle le is associated with a splice variant of GP, and enhanced signal transduct ion. Pie hypothesized that patients carrying the 825T allele exhibit the mo dified G beta(3) phenotype. The resulting enhancement of signal transductio n should be detectable in the G beta gamma-dimer-mediated acetylcholine-sti mulated K+ current (I-K,I-ACh) Methods and Results-Seventy patients undergoing cardiac surgery were genoty ped for the C825T polymorphism. In right atrial myocytes from these patient s, 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 wit h depolarizing ramp pulses and quantified as inward current at - 100 mV; me an amplitudes were (pA/pF) 4.98 +/-0.49 (n =30/93 patients/cells) in patien ts with CC genotype, 4.25+/-0.36 (n=31/121 patients/cells) with TC, and 7.4 6+/-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 pat ients 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 a mplitude of human atrial I-KI and I-K,I-ACh. Increased background current d ensity in TT carriers could shorten action potential duration and may be du e to I-K,I-ACh being constitutively active in this genotype.