Aging reduces the number and function of L-type calcium channels in the membrane of cardiac pacemaker cells.

Abstract

Every heartbeat is initiated by a spontaneous electrical signal generated inside the cardiac pacemaker. The generation of this electrical signal depends on the coordinated opening and closing of different ion channels, where voltage-gated L-type calcium channels play a central role. Despite the reliability of the pacemaker, all mammals experience a linear slowdown of the pacemaker rate with age. In humans, this slowing can become pathological and constitutes the main cause for the requirement of the implantation of artificial pacemakers. However, the mechanisms behind the age-associated slowdown of the pacemaker are not well understood. Here, we show that age alters L-type calcium channels in pacemaker cells from mice. The age-associated alterations include: i) a reduction in the density of the channels at the plasma membrane, ii) a reduction in the clustering of the channels, and iii) a decrease in channel open probability. Altogether, these age-associated alterations result in a global reduction of the L-type calcium current density and in a slowdown of the pacemaker diastolic depolarization. Remarkably, increasing the open probability of L-type calcium channels pharmacologically was enough to restore pacemaker rate in old cells to the same levels observed in the young. Overall, our findings provide evidence that proper organization and function of L-type calcium channels is impaired by aging and that this dysfunction contributes to the slowdown of pacemaker cells in old animals.