T-type channels in the sino-atrial and atrioventricular pacemaker mechanism

Cardiac automaticity is a fundamental physiological function in vertebrates. Heart rate is under the control of several neurotransmitters and hormones and is permanently adjusted by the autonomic nervous system to match the physiological demand of the organism. Several classes of ion channels and proteins involved in intracellular Ca2+ handling contribute to pacemaker activity. Voltage-dependent T-type Ca2+ channels are an integral part of the complex mechanism underlying pacemaking. T-type channels also contribute to impulse conduction in mice and humans. Strikingly, T-type channel isoforms are co-expressed in the cardiac conduction system with other ion channels that play a major role in pacemaking such as f- (HCN4) and L-type Ca(v)1.3 channels. Pharmacologic inhibition of T-type channels reduces the spontaneous activity of isolated pacemaker myocytes of the sino-atrial node, the dominant heart rhythmogenic centre. Target inactivation of T-type Ca(v)3.1 channels abolishes I (Ca,T) in both sino-atrial and atrioventricular myocytes and reduces the daily heart rate of freely moving mice. Ca(v)3.1 channels contribute also to automaticity of the atrioventricular node and to ventricular escape rhythms, thereby stressing the importance of these channels in automaticity of the whole cardiac conduction system. Accordingly, loss-of-function of Ca(v)3.1 channels contributes to severe form of congenital bradycardia and atrioventricular block in paediatric patients.