PubMed 11714649

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Kir2.1 , Kir2.4 , Kir3.4

Title: Molecular basis of downregulation of G-protein-coupled inward rectifying K(+) current (I(K,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced I(K,ACh) and muscarinic receptor-mediated shortening of action potentials.

Authors: D Dobrev, E Graf, E Wettwer, H M Himmel, O Hála, C Doerfel, T Christ, S Schüler, U Ravens

Journal, date & volume: Circulation, 2001 Nov 20 , 104, 2551-7

PubMed link:

Clinical and experimental evidence suggest that the parasympathetic nervous system is involved in the pathogenesis of atrial fibrillation (AF). However, it is unclear whether changes in G-protein-coupled inward rectifying K(+) current (I(K,ACh)) contribute to chronic AF.In the present study, we used electrophysiological recordings and competitive reverse-transcription polymerase chain reaction to study changes in I(K,ACh) and the level of the I(K,ACh) GIRK4 subunit in isolated human atrial myocytes and the atrial tissue of 39 patients with sinus rhythm and 24 patients with chronic AF. The density of I(K,ACh) was approximately 50% smaller in myocytes from patients with AF compared with those in sinus rhythm, and this was accompanied by decreased levels of GIRK4 mRNA. The current density of the inward rectifying K(+) current (I(K1)) was 2-fold larger during AF than in sinus rhythm, in correspondence with an increase in Kir2.1 mRNA. The larger I(K1) in AF is consistent with more negative membrane potentials in right atrial trabeculae from AF patients. Moreover, action potential duration was reduced in AF, and the action potential shortening produced by muscarinic receptor stimulation was attenuated, indicating that the changes of I(K1) and I(K,ACh) were functionally relevant.Chronic human AF induces transcriptionally mediated upregulation of I(K1) but downregulation of I(K,ACh) and attenuates the muscarinic receptor-mediated shortening of atrial action potentials. This suggests that atrial myocytes adapt to a chronically high rate by downregulating I(K,ACh) to counteract the shortening of the atrial effective refractory period due to electrical remodeling.