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

Molecular and electrical remodeling of ion channels determining action potential duration has been proposed as a major mechanism in chronic atrial fibrillation. We investigated the mRNA expression of the cardiac L-type Ca(2+)-channel 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-hydroxytryptamine type 4-, beta (1)-, and beta (2)-adrenergic receptors, which are known to stimulate the L-type Ca(2+)-current in human atrium, was analyzed and the effect of chronic beta -blocker treatment on the mRNA expression of these receptors and of the L-type Ca(2+)-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 with chronic atrial fibrillation, there were only mild reductions in mRNA expression of the alpha (1c)-subunit (-15.5%, p = 0.13), and of the beta (1)-subunit isoforms a and c (-13.3%, p = 0.14 and -16.6%, p = 0.18, respectively). 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 significantly reduced in patients with chronic AF. Taken together, the mRNA expression of the <beta>(1)-subunit isoforms b and c, which are splice variants, 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 shift 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-HT(4)-receptor transcript was significantly reduced by 36% (p < 0.05). The <beta>-adrenoreceptor transcription was unchanged. In both SR and AF patients, chronic beta -blocker treatment did neither significantly effect the mRNA expression of the L-type Ca(2+)-channel subunits, the beta -adrenoreceptor subtypes 1 and 2, nor that of the 5-HT(4)-receptor. Our data show that chronic AF is associated with a decrease in the atrial mRNA amount of auxiliary subunits of the L-type Ca(2+)-channel and of the 5-HT(4)-receptor. This supports the hypothesis that the observed alterations in mRNA transcription in AF patients may lead to a decrease in the availability of functional L-type Ca(2+)-channels and 5-HT(4)-receptors and/or reduce L-type Ca(2+)-current amplitude and density, thus, promoting and stabilizing the arrhythmia.