Functional role of L-type Ca _v 1.3 Ca ²⁺ channels in cardiac pacemaker activity

Abstract

The spontaneous activity of pacemaker cells in the sino-atrial node (SAN) controls the heart rhythm and rate under physiological conditions. Pacemaker activity in SAN cells is due to the presence of the diastolic depolarization, a slow depolarization phase that drives the membrane voltage from the end of an action potential to the threshold of a new action potential. SAN cells express a wide array of ionic channels, but we have limited knowledge about their functional role in pacemaker activity and we still do not know which channels play a prominent role in the generation of the diastolic depolarization. It is thus important to provide genetic evidence linking the activity of genes coding for ionic channels to specific alterations of pacemaker activity of SAN cells. Here, we show that target inactivation of the gene coding for ␣1D (Cav1.3) Ca 2؉ channels in the mouse not only significantly slows pacemaker activity but also promotes spontaneous arrhythmia in SAN pacemaker cells. These alterations of pacemaker activity are linked to abolition of the major component of the L-type current (I Ca,L) activating at negative voltages. Pharmacological analysis of I Ca,L demonstrates that Cav1.3 gene inactivation specifically abolishes I Ca,L in the voltage range corresponding to the diastolic depolarization. Taken together, our data demonstrate that Ca v1.3 channels play a major role in the generation of cardiac pacemaker activity by contributing to diastolic depolarization in SAN pacemaker cells.

G protein-gated I KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

“…In addition, Ca v 1.3 −/− mice reproduce severe AV dysfunction typical of human congenital heart block (16). Previous studies demonstrated that Ca v 1.3-mediated I Ca,L plays a major role in the determination of heart rate and impulse conduction in mice and humans (10,11,14,16,17,19). However, despite the importance of Ca v 1.3-mediated I Ca,L in determining the rate of the diastolic depolarization in isolated SAN and AV node myocytes (14,16), it was unclear how Ca v 1.3 loss of function translates into SSS in vivo.…”

“…myocytes, thereby constituting important determinants of heart rate and AV conduction velocity (14,16). The heart rate of mice lacking Ca v 1.3 channels (Ca v 1.3 −/− mice) fairly recapitulates the hallmarks of SSS and associated symptoms, including bradycardia and tachycardia-bradycardia syndrome (17,18).…”

“…In mice and humans, Ca v 1.3 channels are expressed in the SAN, atria, and the AV node but are absent in adult ventricular tissue (14,15). Ca v 1.3-mediated I Ca,L plays a major role in the generation of the diastolic depolarization in SAN and AV…”

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

“…The inactivated Ca V 1.3 channels in mice induced strong reduction of calcium current in pacemaker cells and profoundly affected its pacemaking effect, which showed predominant sinoatrial nodal dysfunction [124]. With the inactivated Ca V 1.3 calcium currents, both sinoatrial arrhythmia and bradycardia have been observed [23,125].…”

Potassium channels in the sinoatrial node and their role in heart rate control

“…In the initial phase this is mediated by sodium influx via I f , largely constituted by the HCN4 subunit, and as depolarization occurs progressively by T-type calcium channels and finally L-type calcium channels, specifically Ca v 1.3, just prior to threshold and initiation of phase 0. Ca v 1.3 knockout mice have highly unstable pacemaker function with bradycardia and episodes of sinus pauses [12]. The major T-type subunit in the adult animal is Ca v 3.1 and knockout mice are bradycardic [13].…”