Cardiac T-type Ca2+ channels in the heart

Two different Ca2+ channels exist in cardiac myocytes. While the L-type Ca2+ channel is ubiquitous and the main source of Ca2+ for excitation–contraction coupling and pacemaker activity, the functional role of the T-type Ca2+ channel is diverse and depends on mammalian species, heart region, age and various cardiac diseases. Two isoforms of T-type Ca2+ channel proteins in the heart, CaV3.1 and CaV3.2, are functionally expressed in embryonic hearts, but markedly diminish during development. In the adult heart, the T-type Ca2+ channel is almost undetectable in ventricular myocytes and is most prevalent in the conduction system, playing a functional role in facilitating pacemaker depolarization of the sinoatrial node. Interestingly, the T-type Ca2+ channel is re-expressed in atrial and ventricular myocytes under various pathological conditions such as hypertrophy and heart failure, and contributes to abnormal electrical activity and excitation–contraction coupling, but the T-type channel provides a smaller contribution to the trigger for Ca2+ release than does the L-type Ca2+ channel. Instead, the T-type Ca2+ channel has been shown to play a crucial role in the process of pathological cardiac hypertrophy. Increased Ca2+ influx via CaV3.2, the T-type Ca2+ channel, induces calcineurin/NFAT (nuclear factor of activated T-cell) hypertrophic signaling. Furthermore, new evidence has been accumulating on the regulatory mechanism of T-type Ca2+ channel expression, including the neuron restrictive silencer element–neuron restrictive silencer factor (NRSE–NRSF) system, mitogen activated protein (MAP) kinases and cardiac homeobox transcription factor Csx/Nkx2.5. This review summarizes our present knowledge regarding cardiac T-type Ca2+ channels, and discusses their pathophysiological significance in the heart.