Abstract
Atrial fibrillation (AF) is a significant contributor to cardiovascular morbidity and mortality. The currently available treatments are limited and AF continues to be a major clinical challenge. Clinical studies have shown that AF is frequently associated with dysfunction in the sino-atrial node (SAN). The association between AF and SAN dysfunction is probably related to the communication between the SAN and the surrounding atrial cells that form the SAN-atrial pacemaker complex and/or pathological processes that affect both the SAN and atrial simultaneously. Recent evidence suggests that Ca2+ entry through TRPC3 (Transient Receptor Potential Canonical-3) channels may underlie several pathophysiological conditions -including cardiac arrhythmias. However, it is still not known if atrial and sinoatrial node cells are also involved. In this article we will first briefly review TRPC3 and IP3R signaling that relate to store/receptor-operated Ca2+ entry (SOCE/ROCE) mechanisms and cardiac arrhythmias. We will then present some of our recent research progress in this field. Our experiments results suggest that pacing-induced AF in angiotensin II (Ang II) treated mice are significantly reduced in mice lacking the TRPC3 gene (TRPC3−/− mice) compared to wild type controls. We also show that pacemaker cells express TRPC3 and several other molecular components related to SOCE/ROCE signaling, including STIM1 and IP3R. Activation of G-protein coupled receptors (GPCRs) signaling that is able to modulate SOCE/ROCE and Ang II induced Ca2+ homeostasis changes in sinoatrial complex being linked to TRPC3. The results provide new evidence that TRPC3 may play a role in sinoatrial and atrial arrhythmias that are caused by GPCRs activation.
Highlights
The Role of Intracellular ca2+ in Sinoatrial Arrhythmias In the normal heart, pacemaker cells in the sinoatrial node (SAN) generate spontaneous membrane depolarizations that trigger action potentials, which propagate through the conduction system to initiate atrial and ventricular cell depolarization and contraction
Evidence for Transient Receptor Potential Canonical-3 (TRPC3) Involvment in Atrial Arrhythmias angiotensin II (Ang II) signaling pathways lead to a hypertrophy which seems to be related to TRPC3 expression (Onohara et al, 2006)
To examine whether TRPC3 is involved in atrial fibrillation (AF) induced by Ang II, we induced AF in mice by pacing Langendorff-perfused hearts from WT and TRPC3−/− KO mice which had been treated with Ang II (See Methods) over of 10–14 days
Summary
The Role of Intracellular ca2+ in Sinoatrial Arrhythmias In the normal heart, pacemaker cells in the sinoatrial node (SAN) generate spontaneous membrane depolarizations that trigger action potentials, which propagate through the conduction system to initiate atrial and ventricular cell depolarization and contraction. In contrast to normal pacemaker activity, abnormal arrhythmogenic electrical activity can arise in ectopic sites due to impulse re-entry or abnormal spontaneous membrane depolarizations (Nattel, 2002). While it is clear that cardiac arrhythmias, including SAN dysfunction and atrial fibrillation (AF), are multifactorial there is increasing experimental evidence for abnormal Ca2+ handling being a key factor (Dobrev and Nattel, 2008; Yeh et al, 2008) and is the focus of this paper. The most prominent Ca2+-dependent ionic current during pacemaker activity is the Na/Ca exchange (NCX) current which contributes to pacemaker current(s) but may produce arrhythmogenic electrical activity (Sipido et al, 2006) which is related to abnormalities in Ca2+ handling leading to abnormal NCX currents (Hove-Madsen et al, 2004; Vest et al, 2005). Activation of GPCRs by agonists such as angiotensin II (Ang II)
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