Genesis and Regulation of the Heart Automaticity

Abstract

The heart automaticity is a fundamental physiological function in higher organisms. The spontaneous activity is initiated by specialized populations of cardiac cells generating periodical electrical oscillations. The exact cascade of steps initiating the pacemaker cycle in automatic cells has not yet been entirely elucidated. Nevertheless, ion channels and intracellular Ca(2+) signaling are necessary for the proper setting of the pacemaker mechanism. Here, we review the current knowledge on the cellular mechanisms underlying the generation and regulation of cardiac automaticity. We discuss evidence on the functional role of different families of ion channels in cardiac pacemaking and review recent results obtained on genetically engineered mouse strains displaying dysfunction in heart automaticity. Beside ion channels, intracellular Ca(2+) release has been indicated as an important mechanism for promoting automaticity at rest as well as for acceleration of the heart rate under sympathetic nerve input. The potential links between the activity of ion channels and Ca(2+) release will be discussed with the aim to propose an integrated framework of the mechanism of automaticity.

The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

“…We also identified a common variant in CAC-NA1D (SNP rs312480) to be associated with reduced fasting insulin and putatively also with 30 min insulin levels, indicating that this isoform might not strictly participate in phasic but also in basal insulin secretion. In fact, Ca v 1.3, with its lower activation threshold compared with Ca v 1.2 [10], has been suggested to be involved in pacemaking in the heart [41] and in the neuroendocrine chromaffin cell [42]. Considering that the neuroendocrine beta cell also fires action potentials in the physiological resting (or preprandial) condition [43], Ca v 1.3, with its low activation threshold, might be a good candidate for these events.…”

Control of heart rate by cAMP sensitivity of HCN channels

“…SAN activity is controlled by the autonomic nervous system; cholinergic and ␤-adrenergic stimulation either slows or accelerates spontaneous SAN activity. Several ionic currents contribute to cardiac automaticity (4)(5)(6). Some of these currents are targets of regulation by the autonomic nervous system, but their physiological importance is a matter of debate (4,5).…”

“…Several ionic currents contribute to cardiac automaticity (4)(5)(6). Some of these currents are targets of regulation by the autonomic nervous system, but their physiological importance is a matter of debate (4,5). ''Pacemaker'' f-channels mediating the hyperpolarizationactivated nonselective cation current I f , in particular, are directly regulated by cAMP (7).…”

“…Although these biophysical properties seem to make f-channels ideal molecular targets for heart rate regulation, the contribution of the major I f -mediating cardiac isoforms HCN2 and HCN4 to SAN function remains highly controversial. Although human genetic (9)(10)(11)(12) and pharmacologic (5,13,14) studies suggest a significant role for HCN4 subunits in SAN pacemaking in humans and rodents, recent data from transgenic mouse models have challenged this view (15,16). Targeted deletion of HCN4 in adult mice was found to cause heart ratedependent sinus pauses but to have no effect on either basal or maximal heart rate or heart rate regulation (16).…”

Rôle des phosphodiestérases des nucléotides cycliques de types 3 et 4 dans le couplage excitation-contraction et les arythmies cardiaques

“…Le niveau d'expression des quatre familles présente une grande variabilité inter-espèce et dépend également du de la relaxation cardiaque (effet lusitrope positif) [2]. En plus de la PKA, l'AMPc peut activer les canaux HCN (hyperpolarisation-activated cyclic nucleotide-gated channels) impliqués dans la régulation de la fréquence cardiaque [3,4], et le facteur d'échange des petites protéines G Rap, Epac (exchange protein activated by cAMP), impliqué dans l'hypertrophie cardiaque [5,6]. Des travaux récents proposent qu'Epac participe aussi à la régulation du CEC en régulant la sortie de Ca 2+ des RyR2 [7] et l'affinité des myofilaments pour le Ca 2+ [8].…”