Expression and roles of Cav1.3 (α1D) L-Type Ca2+ Channel in atrioventricular node automaticity

Abstract

Atrioventricular node (AV node) is the hub where electrical input from the atria is propagated and conveyed to the ventricles. Despite its strategic position and role in governing impulse conduction between atria and ventricles, there is paucity of data regarding the contribution of specific ion channels to the function of the AV node. Here, we examined the roles of Cav1.3 L-type Ca2+ channel in AV node by taking advantage of a mouse model with null mutation of Cav1.3 (Cav1.3−/−). Cav1.3 null mutant mice show evidence of AV node dysfunction with AV block, suggesting the tissue-specific function of the Cav1.3 channel. In keeping with this assertion, we demonstrate that Cav1.3 isoform is highly expressed in the isolated AV node cells. Furthermore, AV node isolated from Cav1.3 null mutant mice show a significant decrease in the firing frequency of spontaneous action potentials suggesting that Cav1.3 L-type Ca2+ channel plays significant roles in the automaticity of the AV node. Because of the distinct voltage-dependence of Cav1.2 and Cav1.3 Ca2+ channels, Cav1.2 alone does not suffice to maintain normal AV node function. Cav1.3 currents activate at more hyperpolarizing voltage compared to Cav1.2 currents. Consequently, Cav1.2 Ca2+ channel cannot functionally substitute for Cav1.3 isoform in the AV node of Cav1.3 null mutant mice. Thus, our study demonstrates that the distinct biophysical properties of Cav1.3 Ca2+ channel play critical roles in the firing frequency of AV node tissues.

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

“…Pharmacologically, there are currently no reagents available to discriminate between the two distinct currents, but they can be distinguished based on their voltagedependent activation. Ca v 1.2 channels exhibit slower activation kinetics, which occurs at more depolarizing membrane potentials than for Ca v 1.3 [66,67] . ECG performed on Ca v 1.3 -/ -null mutant mice revealed bradycardia, SAN dysfunction and an AV block [68] .…”

“…ECG performed on Ca v 1.3 -/ -null mutant mice revealed bradycardia, SAN dysfunction and an AV block [68] . APs that were spontaneously recorded from isolated SAN or AVN cells also showed a decrease in the pacing rate and the DD slope, pointing to the important role of these channels in the pacemaker function [65,67] . Recently, different transient receptor potential (TRPM) channels have also been described as having a role in this physiological process.…”

“…A typical trace of an ECG shows the "P-wave", the "P-Q interval" (isoelectric line), the "QRS complex", the "T-wave" and the "U-wave". [60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75] in the SAN). This "SAN overdrive suppression" on the other elements of the conductive network explains its leading role in driving the pacemaker.…”

Regulation of Gene Transcription by Voltage-gated L-type Calcium Channel, Cav1.3

“…Moreover, Ca v 1.3 is preferentially expressed in atrial compared with ventricular myocytes. Indeed, the importance of the Ca v 1.3 isoform is underscored by the findings that Ca v 1.3 null mutant mice (Ca v 1.3 Ϫ/Ϫ ) show significant alteration in atrial excitability and atrial fibrillation, as well as sinoatrial and atrioventricular node dysfunction (1)(2)(3)(4)(5). These observations were surprising, yet insightful as they suggest that detailed knowledge of the different Ca 2ϩ channel isoforms may have broad therapeutic ramifications in the treatment of atrial arrhythmias.…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…Moreover, alternative splicing in Ca V 1.2 channels make some roles in several cardiovascular diseases, including cardiac arrhythmia [15–17]. Ca V 1.3 α 1D ( CACNA1D ) is highly expressed in both SANCs and cochlear inner hair cells [18–21]. Targeted deletion of α 1D caused deafness, pronounced bradycardia, and nonfatal sinoatrial arrhythmia in mice [22,23].…”