Bradycardia and Slowing of the Atrioventricular Conduction in Mice Lacking Ca _V 3.1/α _1G T-Type Calcium Channels

Abstract

The generation of the mammalian heartbeat is a complex and vital function requiring multiple and coordinated ionic channel activities. The functional role of low-voltage activated (LVA) T-type calcium channels in the pacemaker activity of the sinoatrial node (SAN) is, to date, unresolved. Here we show that disruption of the gene coding for CaV3.1/alpha1G T-type calcium channels (cacna1g) abolishes T-type calcium current (I(Ca,T)) in isolated cells from the SAN and the atrioventricular node without affecting the L-type Ca2+ current (I(Ca,L)). By using telemetric electrocardiograms on unrestrained mice and intracardiac recordings, we find that cacna1g inactivation causes bradycardia and delays atrioventricular conduction without affecting the excitability of the right atrium. Consistently, no I(Ca,T) was detected in right atrium myocytes in both wild-type and CaV3.1(-/-) mice. Furthermore, inactivation of cacna1g significantly slowed the intrinsic in vivo heart rate, prolonged the SAN recovery time, and slowed pacemaker activity of individual SAN cells through a reduction of the slope of the diastolic depolarization. Our results demonstrate that CaV3.1/T-type Ca2+ channels contribute to SAN pacemaker activity and atrioventricular conduction.

Different distribution of Cav3.2 and Cav3.1 transcripts encoding T-type Ca2+ channels in the embryonic heart of mice

“…OT: Outflow Tract, A: Atrium, V: Ventricle, AVC: AV canal, Vertical axis: normalized molecules/GAPDH mRNA that Cav3.2 plays an important role in the generation of both the atrio-ventricular conduction system and the outflow tract on the stage of chamber-specification. Cav3.1 was necessary for the formation of conduction system especially, of which notion was supported by the previous report (10). Nkx2.5 is expressed throughout the development of the heart primordium.…”

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

“…In fact, Ca v 3.1 knockout mice display arrhythmias, such as bradycardia, and an AVN delay in ECG. Spontaneous action potentials recorded from isolated SAN or AVN cells from the Ca v 3.1 knockout mice have a shallower DD slope and a lower instantaneous firing rate than wild-type cells [64] . Given that wild-type cells are activated by hyperpolarizing membrane voltages, the inward currents of these channels can contribute to the pacemaker slope ( Figure 3, left panel).…”

“…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.…”

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

“…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]. This slow diastolic depolarization is opposed by inward rectifier potassium currents and other background currents (see below).…”