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 encoding for the beta(3)-subunit of heterotrimeric G proteins. The 825T allele is associated with a splice variant of Gbeta(3) and enhanced signal transduction. We hypothesized that patients carrying the 825T allele exhibit the modified Gbeta(3) phenotype. The resulting enhancement of signal transduction should be detectable in the Gbetagamma-dimer-mediated acetylcholine-stimulated K(+) current (I(K,ACh)).


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 micromol/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 Gbeta(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.
Department of Pharmacology and Toxicology, Medical Faculty, University of Technology, Dresden, Germany.
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D
Dobrev
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Wettwer
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Himmel
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Kortner
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Kuhlisch
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Schüler
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Siffert
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Ravens
D000368:Aged; D000483:Alleles; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D005838:Genotype; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006325:Heart Atria; D006331:Heart Diseases / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics; D015221:Potassium Channels / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying
D002121:Calcium Channel Blockers; D018679:Cholinergic Agonists; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D002217:Carbachol; D019204:GTP-Binding Proteins