Impaired Ca²⁺ homeostasis is associated with atrial fibrillation in the α_1D L-type Ca²⁺ channel KO mouse

Abstract

current (ICa-L) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the ␣1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the ␣ 1D Ca 2ϩ channel to the global ICa-L, the intracellular Ca 2ϩ transient, the Ca 2ϩ handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from ␣1D KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated ␣1D KO atrial myocytes revealed a significant reduction of ICa-L (24.5%; P Ͻ 0.05). However, there were no changes in other currents such as INa, ICa-T, IK, If, and Ito and no changes in ␣1C mRNA levels of ␣1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca 2ϩ transient (ϳ40%; P Ͻ 0.05) and rapid caffeine application caused a 17% reduction of the SR Ca 2ϩ content (P Ͻ 0.05) and a 28% reduction (P Ͻ 0.05) of fractional SR Ca 2ϩ release in ␣1D KO atria. In conclusion, genetic deletion of ␣1D Ca 2ϩ channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the ␣1D KO mice were associated with a decrease in the total ICa-L density, a reduction in intracellular Ca 2ϩ transient, and impaired intracellular Ca 2ϩ handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the ␣1D KO mice. mice; calcium transient; arrhythmia; myocyte THE VOLTAGE-GATED ␣ 1D Ca 2ϩ channel was previously considered to be expressed only in cells of neuroendocrine origin (10). Recent studies (11,15,16,19,26) reported that the ␣ 1D deletion in mice causes sinus bradycardia and various degrees of atrioventricular (AV) block. The evidence presented suggests a critical role of the ␣ 1D Ca 2ϩ channel in diastolic depolarization and in the rate of discharge of the sinoatrial (SA) node. The expression of ␣ 1D Ca 2ϩ channel was demonstrated in the SA node, AV node, and atria, but not in the ventricles of adult hearts (15,20,26). Therefore, deletion of ␣ 1D Ca 2ϩ channel could play an important role in altering the normal activity of the atrium and might also contribute to atrial arrhythmias, such as atrial fibrillation (AF).AF is the most common cardiac arrhythmia, and it is associated with a four-to fivefold increase in the risk of stroke compared with the general population. It affects an estimated 2.2 million adults in the United States (4). Because of its clinical relevance and the lack of an effective therapy, many experimental models of AF have been tested to elucidate the mechanisms of initiation and maintenance of AF. A decreased L-type Ca 2ϩ current (I Ca-L ) density is a common finding and has been reported in several models of AF (23,25).Unlike ventricular cells, a unique property of atrial cells is that both ␣ 1C and ␣ 1D Ca 2ϩ channels contribute to the tota...

MicroRNA-328 Contributes to Adverse Electrical Remodeling in Atrial Fibrillation

“…In agreement with this notion, Mancarella et al 15 have shown that knockout of ␣ 1D (another ␣ subunit of atrial L-type Ca 2ϩ channel) alone is sufficient to cause atrial ECG abnormalities and to enhance AF vulnerability in the absence of changes of other currents such as I Na , I Ca-T , I K , I f , and I to . Moreover, atrial tachyarrhythmias cause atrial mechanical dysfunction related to abnormal handling of cellular Ca 2ϩ , which contributes to thrombus formation.…”

“…Indeed, it has been shown that ␣ 1D (an ␣ subunit of atrial L-type Ca 2ϩ channel) knockout mice had atrial ECG abnormalities and enhanced AF vulnerability. 15 Although expression deregulation of Ca 2ϩ channel-encoding genes in AF has been documented, the molecular determinants have remained incompletely understood.…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Thus far, it is unclear to what extent other CACNA1D mutations or polymorphisms contribute risk for hearing disorders or for SAN dysfunction. Despite a normal life span, Ca V 1.3 2/2 mice also appear more vulnerable to ventricular extrasystoles (Matthes et al, 2004) and atrial fibrillation due to reduced L-type currents and impaired intracellular Ca 2+ handling in atrial myocytes (Zhang et al, 2002;Mancarella et al, 2008). c. Neuropsychiatric Disease.…”

The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance

“…These mutations are likely to reduce greatly or even abolish the function of the encoded gene product. Ca v 1.3 (a1D) is a key regulator of calcium homeostasis, electrical activity, and maintenance of normal rhythm in the heart (Chahine et al 2008;Mancarella et al 2008), and in Cacna1d knockout mice, gene deletion is associated with hypoinsulinaemia, glucose intolerance, and decreased number and size of pancreatic islets (Namkung et al 2001). It is therefore of interest that genome-wide association analysis in humans has shown an association between polymorphism in the Cacna1d gene and type 2 diabetes (Sookoian et al 2009) and suggests that investigation of the functional consequences of Cacna1d mutations in SHR/OlaIpcv would be worthwhile.…”