Review article
Cardiac T-type Ca2+ channels in the heart

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Abstract

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.

Introduction

The physiological importance of voltage-dependent Ca2+ influx was first recognized by Fatt and Katz in 1953 [1], and was subsequently studied and confirmed by Hagiwara et al. in 1975 [2]. In the heart, voltage-dependent Ca2+ channels are thought to mediate Ca2+ influx in response to membrane depolarization and regulate excitability, contraction, hormonal secretion and possibly gene transcription. In the 1980s, two distinct Ca2+ channels were for the first time recorded in cardiac myocytes: L-type and T-type Ca2+ channels. The T-type Ca2+ channel is characterized by a low voltage-activated, transient-type Ca2+ channel in contrast to the high voltage-activated, long-lasting L-type Ca2+ channel [3], [4]. In the heart, the L-type Ca2+ channel is the most abundant and is responsible for Ca2+ entry into the cell, which triggers contraction. On the other hand, the T-type Ca2+ channel was initially considered to play only a minor functional role because of its small amplitude and transient nature [5], [6]. However, the discovery of T-type Ca2+ channel antagonists and the cloning of three isoforms CaV3.1–3.3 in the 1990s advanced the development of T-type Ca2+ channel research significantly [7], [8]. Indeed, it is now well known that the T-type Ca2+ channel contributes significantly to cardiac automaticity, development and excitation–contraction coupling in normal cardiac myocytes. Furthermore, its functional role becomes more marked in the process of pathological cardiac hypertrophy and heart failure.

Section snippets

Molecular basis of T-type Ca2+ channels

Voltage-dependent Ca2+ channels are electrophysiologically divided into two major classes: low voltage-activated and high voltage-activated Ca2+ channels. According to the pharmacological and biophysical properties of voltage-dependent Ca2+ channels, they are subdivided into five groups (P/Q, N, L, R, and T), and the low voltage-activated channel class consists of only T-type Ca2+ channels which open at low membrane potentials and inactivate very rapidly [9], [10]. L-type and T-type Ca2+

Kinetics and conductance of T-type Ca2+ channels in native cardiac myocytes

T-type Ca2+ channels can be distinguished from L-type Ca2+ channels on the basis of their distinctive gating and conductance properties [10] (Fig. 1). Compared with L-type Ca2+ channels, T-type Ca2+ channels open at significantly more negative membrane potentials that overlap the pacemaker potentials of sinoatrial node cells [15]. The threshold for activation of ICaT is −70 to −60 mV and ICaT is fully activated at −30 to −10 mV at physiological Ca2+ concentration [8], [11], [15]. The time

Developmental change in T-type Ca2+ channel expression

The current density and expression levels of T-type Ca2+ channels changes during the fetal period, and the T-type Ca2+ channels contribute to electrical activity in the early embryonic heart. It has been reported that Cav3.1 underlies functional T-type Ca2+ channels in mouse hearts at the middle embryonic stage [26], and that both Cav3.1 and Cav3.2 participate in the functional T-type Ca2+ channels in rat hearts at the middle embryonic to perinatal stages [27]. Niwa et al. [28] have shown that

Modulation of T-type Ca2+ channels by neurotransmitters and hormones

The activity of cardiac T-type channels is affected by various neurotransmitters and hormones including endothelin, bradykinin, ATP, α1-adrenergic agonists and so on (for review, see [11], [30]). Some of these substances appeared to be mediated by a PKC-dependent mechanism, while there are some controversies for the effects of PKC on ICaT, i.e., endothelin increased ICaT in rat ventricular cells via a protein kinase C (PKC)-dependent mechanism while PKC decreased ICaT in other studies [10], [11]

Contribution of T-type Ca2+ channels to cardiac pacemaking

As T-type Ca2+ channels are most prevalent in the conduction system in the adult heart and the activation range of ICaT overlaps the pacemaker potential, it has been suggested that T-type Ca2+ channels play a role in generating pacemaker depolarization and in contributing to automaticity [14], [16]. In the original studies by Hagiwara et al. [14] and Doerr et al. [32], however, blockage of T-type Ca2+ channels using Ni2+ slowed the firing frequency of the rabbit sinoatrial node cell only

Electrical remodeling and pathological significance of T-type Ca2+ channels

Cardiac T-type Ca2+ channels reappear when the heart is subjected to pathological stress that induces cardiac hypertrophy and failure, such as experimental aortic banding, myocardial infarction, and chronic exposure to endothelin-1, angiotensin II or aldosterone (for review, see ref. [11]). The increased ICaT in rat ventricle usually showed relatively high Ni2+ sensitivity, a characteristic feature of CaV3.2-related ICaT, whereas CaV3.2 mRNA remained unchanged and CaV3.1 mRNA was increased in

Concluding remarks

This review aims at highlighting the increasing evidence for a functional role of T-type Ca2+ channels in cardiac automaticity, development and excitation–contraction coupling in normal cardiac myocytes, and also in the process of pathological cardiac hypertrophy and heart failure. These previous years, some in vivo and in vitro studies on T-type channels have provided evidence for the implication of some mediators in T-type channel expression in hypertrophied myocytes, including the NRSE–NRSF

Acknowledgment

This work was supported by the Vehicle Racing Commemorative Foundation.

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