Atrial L-type Ca2+-channel, beta-adrenoreceptor, and 5-hydroxytryptamine type 4 receptor mRNAs in human atrial fibrillation

Molecular and electrical remodeling of ion channels determining action pote ntial duration has been proposed as a major mechanism in chronic atrial fib rillation. We investigated the mRNA expression of the cardiac L-type Ca2+-c hannel subunits alpha (1c), alpha (2)/delta (1), beta (1a), and beta (1b/c) in atrial tissue of patients with chronic atrial fibrillation compared to patients in sinus rhythm. In addition, the mRNA expression of the 5-hydroxy tryptamine type 4-, beta (1)-, and beta (2)-adrenergic receptors, which are known to stimulate the L-type Ca2+-current in human atrium, was analyzed a nd the effect of chronic beta -blocker treatment on the mRNA expression of these receptors and of the L-type Ca2+-channel subunits was assessed. Total RNA was isolated from right atrial appendages of patients in sinus rhythm and of patients with chronic atrial fibrillation. Then, semiquantitative RT -PCR using 18S RNA as the "housekeeping gene" was performed. In patients wi th chronic atrial fibrillation, there were only mild reductions in mRNA exp ression of the alpha (1c)-subunit (-15.5%, p = 0.13), and of the beta (1)-s ubunit isoforms a and c (-13.3%, p = 0.14 and -16.6%, p = 0.18, respectivel y). However, mRNA expression of the alpha (2)/delta (1)-subunit (-31.5%, p < 0.01) and of the <beta>(1)-subunit isoform b (-39.9%, p < 0.0005) was sig nificantly reduced in patients with chronic AF. Taken together, the mRNA ex pression of the <beta>(1)-subunit isoforms b and c, which are splice varian ts, was significantly down-regulated by 26.5% (p < 0.05) in these patients. The analysis of the <beta>(1c)/beta (1b) ratio resulted in a significant s hift by 39.2% (p < 0.0001) in favor of <beta>(1c) in patients with chronic atrial fibrillation. In the AF patients, the abundance of the 5-HT4-recepto r transcript was significantly reduced by 36% (p < 0.05). The <beta>-adreno receptor transcription was unchanged. In both SR and AF patients, chronic b eta -blocker treatment did neither significantly effect the mRNA expression of the L-type Ca2+-channel subunits, the beta -adrenoreceptor subtypes 1 a nd 2, nor that of the 5-HT4-receptor. Our data show that chronic AF is asso ciated with a decrease in the atrial mRNA amount of auxiliary subunits of t he L-type Ca2+-channel and of the 5-HT4-receptor. This supports the hypothe sis that the observed alterations in mRNA transcription in AF patients may lead to a decrease in the availability of functional L-type Ca2+-channels a nd 5-HT4-receptors and/or reduce L-type Ca2+-current amplitude and density, thus, promoting and stabilizing the arrhythmia.