Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool St, Darlinghurst, NSW 2010, Australia.
Cardiovasc Res. 2011 Jul 15;91(2):310-9. doi: 10.1093/cvr/cvr081. Epub 2011 May 5.
Sympathetic regulation of cardiac contractility is mediated in part by α(1)-adrenergic receptors (ARs), and the α(1A)-subtype has been implicated in the pathogenesis of cardiac hypertrophy. However, little is known about α(1A)-AR signalling pathways in ventricular myocardium. The aim of this study was to determine the signalling pathway that mediates α(1A)-AR-coupled cardiac contractility.
Using a transgenic model of enhanced cardiac α(1A)-AR expression and signalling (α(1A)-H mice), we identified a receptor-coupled signalling pathway that enhances Ca(2+) entry and increases contractility. This pathway involves α(1A)-AR-activated translocation of Snapin and the transient receptor potential canonical 6 (TRPC6) channel to the plasma membrane. In ventricular cardiomyocytes from α(1A)-H and their non-transgenic littermates (or WTs), stimulation with α(1A)-AR-specific agonists resulted in increased Ca(2+), which was dose-related and proportional to the level of α(1A)-AR expression. Blockade of TRPC6 inhibited the α(1A)-AR-mediated increase in Ca(2+) and contractility. External Ca(2+) entry, underlying the Ca(2+) increase, was not due to store-operated Ca(2+) entry but to a receptor-operated mechanism of Ca(2+) entry resulting from α(1A)-AR activation.
These findings indicate that Ca(2+) entry via the α(1A)-AR-Snapin-TRPC6-pathway plays an important role in physiological regulation of cardiac contractility and may be an important target for augmenting cardiac performance.
心脏收缩力的交感调节部分是通过 α(1)-肾上腺素能受体（ARs）介导的，α(1A)-亚型被认为与心肌肥厚的发病机制有关。然而，关于心室心肌中 α(1A)-AR 信号通路知之甚少。本研究旨在确定介导 α(1A)-AR 偶联心脏收缩力的信号通路。
使用增强心脏 α(1A)-AR 表达和信号转导的转基因模型（α(1A)-H 小鼠），我们确定了一种增强 Ca(2+)内流并增加收缩力的受体偶联信号通路。该途径涉及 α(1A)-AR 激活 Snapin 和瞬时受体电位经典型 6（TRPC6）通道向质膜的易位。在 α(1A)-H 及其非转基因同窝仔（或 WT）的心室肌细胞中，α(1A)-AR 特异性激动剂刺激导致 Ca(2+)增加，其剂量相关且与 α(1A)-AR 表达水平成正比。TRPC6 阻断抑制了 α(1A)-AR 介导的 Ca(2+)增加和收缩力。Ca(2+)增加的基础上的外钙内流不是由于储存操纵的 Ca(2+)内流，而是由于 α(1A)-AR 激活导致的受体操纵的 Ca(2+)内流机制。
这些发现表明，通过 α(1A)-AR-Snapin-TRPC6 通路的 Ca(2+)内流在心脏收缩力的生理调节中起着重要作用，可能是增强心脏性能的重要靶点。
