Abstract
Introduction: Upregulation of Kir-based inward rectifiers I K1 and constitutively active acetylcholine-regulated current (I KACh,c ) is a prominent contributor to atrial fibrillation (AF) maintenance. This study assessed occurrence and molecular basis of altered I K1 and I KACh,c in man. Methods: Left atrial samples from mitral valve repair patients (n = 21 AF; n = 20 SR) were studied. Patch-clamp was applied to record currents. Immunoblots and confocal microscopy were used to study protein content and localization. Quantitative real-time PCR was performed to study microRNA and mRNA levels. Results: I K1 and I KACh,c densities were greater in cells from AF than SR patients (at −120 mV: 3.5 ± 2.6 vs. 2.1 ± 1.1 pA/pF for I K1 and 1.3 ± 0.8 vs. 0.4 ± 0.3 pA/pF for I KACh,c ). Kir2.1 protein (underlying I K1 ) was increased by AF (Fig. ) but Kir2.3 was unchanged. Kir2.1 mRNA was increased and Kir2.3 mRNA reduced. Kir3.1 and Kir3.4 (underlying I KACh,c ) protein was unaffected. The inhibitory regulatory G-protein G αi-3 was downregulated, potentially explaining increased free G αγ and I KACh,c . No change in other regulatory proteins (RGS4, calmodulin) or subcellular channel and regulatory proteins localization occurred with AF. Kir2.1 protein expression is known to be downregulated by the microRNA miR-1: miR-1 expression was reduced by AF (Fig. ). Conclusions: Both inward rectifier currents I K1 and I KACh,c are increased in human AF. I K1 changes are caused by increased protein expression through transcriptional and post-transcriptional modifications related to miR-1 downregulation, whereas the increase in I KACh,c is functional, possibly mediated by decreased inhibitory G-protein expression.
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