毒蕈碱型乙酰胆碱受体 1 参与人心房肌细胞的内向整流钾电流，并在慢性心房颤动患者中上调。
Muscarinic type-1 receptors contribute to I in human atrial cardiomyocytes and are upregulated in patients with chronic atrial fibrillation.
机构信息
Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany; Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Department of Pharmacology and Toxicology, Carl Gustav Carus Medical Faculty, Dresden University of Technology, Dresden, Germany.
出版信息
Int J Cardiol. 2018 Mar 15;255:61-68. doi: 10.1016/j.ijcard.2017.12.050. Epub 2017 Dec 22.
BACKGROUND
Basal and acetylcholine-gated inward-rectifier K-currents (I and I, respectively) are altered in atrial fibrillation (AF). G-protein-coupled muscarinic (M) receptors type-2 are considered the predominant receptors activating I. Although a role for G-coupled non-M-receptor subtypes has been suggested, the precise regulation of I by multiple M-receptor subtypes in the human atrium is unknown. Here, we investigated M-receptor-mediated I regulation and its remodeling in chronic AF (cAF).
METHODS AND RESULTS
M-receptor mRNA and protein abundance were increased in atrial cardiomyocyte fractions and atrial homogenates from cAF patients, whereas M-receptor levels were unchanged. The regulation of I by M-receptors was investigated in right-atrial cardiomyocytes using two applications of the M-receptor agonist carbachol (CCh, 2μM), with pharmacological interventions during the second application. CCh application produced a rapid current increase (Peak-I), which declined to a quasi-steady-state level (Qss-I). In sinus rhythm (Ctl) the selective M-receptor antagonists pirenzepine (10nM) and muscarinic toxin-7 (MT-7, 10nM) significantly inhibited CCh-activated Peak-I, whereas in cAF they significantly reduced both Peak- and Qss-I, with no effects on basal inward-rectifier currents in either group. Conversely, the selective M-receptor agonist McN-A-343 (100μM) induced a current similar to the CCh-activated current in Ctl atrial cardiomyocytes pretreated with pertussis toxin to inhibit M-receptor-mediated G-protein signaling, which was abolished by MT-7. Computational modeling indicated that M- and M-receptors redundantly activate I to abbreviate APD, albeit with predominant effects of M-receptors.
CONCLUSION
Our data suggest that G-coupled M-receptors also regulate human atrial I and that their relative contribution to I activation is increased in cAF patients. We provide novel insights about the role of non-M-receptors in human atrial cardiomyocytes, which may have important implications for understanding AF pathophysiology.
背景
基础和乙酰胆碱门控内向整流钾电流（分别为 I 和 I）在心房颤动（AF）中发生改变。G 蛋白偶联毒蕈碱（M）受体 2 型被认为是激活 I 的主要受体。尽管已经提出了 G 偶联非 M 受体亚型的作用，但在人类心房中，多种 M 受体亚型对 I 的精确调节尚不清楚。在这里，我们研究了 M 受体介导的 I 调节及其在慢性 AF（cAF）中的重塑。
方法和结果
在 cAF 患者的右心房肌细胞和心房匀浆中，M 受体 mRNA 和蛋白丰度增加，而 M 受体水平不变。使用 M 受体激动剂 carbachol（CCh，2μM）的两次应用，在第二次应用期间进行药理学干预，研究 M 受体对 I 的调节。CCh 应用产生快速电流增加（峰电流），该电流下降至准稳态水平（Qss-I）。在窦性节律（Ctl）中，选择性 M 受体拮抗剂 pirenzepine（10nM）和 muscarinic 毒素-7（MT-7，10nM）显著抑制 CCh 激活的峰电流，而在 cAF 中，它们显著降低峰电流和 Qss-I，而对两组的基础内向整流电流均无影响。相反，选择性 M 受体激动剂 McN-A-343（100μM）在预先用百日咳毒素处理以抑制 M 受体介导的 G 蛋白信号传导的 Ctl 心房肌细胞中诱导类似于 CCh 激活的电流，该电流被 MT-7 消除。计算建模表明，M-和 M 受体冗余地激活 I 以缩短 APD，尽管 M 受体的作用占主导地位。
结论
我们的数据表明，G 偶联 M 受体也调节人类心房 I，并且在 cAF 患者中，它们对 I 激活的相对贡献增加。我们提供了关于非 M 受体在人类心房肌细胞中的作用的新见解，这对于理解 AF 病理生理学可能具有重要意义。
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