Role of T-type Ca2+ channels in the heart
Introduction
Thirty years have passed since the demonstration by Hagiwara et al. [1] that Ca2+ could permeate through two different channels in starfish egg cells. Ten years later, almost simultaneously, Bean [2] and Nilius et al. [3] described for the first time in cardiac myocytes (under whole-cell patch-clamp in dog atrium and single channel analysis in guinea-pig ventricular cells, respectively) that in the presence of Ba2+ as charge carrier a low-threshold activating, fast-inactivating current coexisted together with a slow-inactivating current having a high activation threshold. The latter, the “classical” Ca2+ current corresponds to the “slow inward current” characterized in cardiac tissues more than 15 years before by Reuter [4] and Rougier et al. [5]. The “new” current was called T- (“tiny”, “transient”) type Ca2+ current, ICaT, following the nomenclature established by Tsien's group, while the “classical” Ca2+ current was denominated L-type (“long lasting”), ICaL. Again, more than 10 years had to pass before the molecular identity of T-type channels was unveiled. We now know that there are three T-type channel isoforms CaV3.1–3.3 (α1G, α1H and α1I), two of which (CaV3.1 and CaV3.2) are expressed in the heart (see [6]).
Section snippets
Occurrence and characteristics of ICaT under control conditions
The two above-mentioned papers [2], [3] characterized for the first time in cardiac cells the major differential properties of Ca2+ currents flowing through these two channels (Fig. 1). T-type currents activated and inactivated at more negative voltage (−30 mV) than L-type currents; aforesaid. T-type currents inactivated faster than L-type currents when Ba2+ was the charge carrier and single channel conductance was smaller for T-type channels (6–8 pS versus 18–25 pS in isotonic extracellular Ba2+
ICaT in developing and remodelled heart
Changes in T-type Ca2+ channel expression levels have been observed during the development of various organs, suggesting their important role at specific stages of fetal life. Particularly, in the heart of most mammalian species, T currents are robustly expressed in embryonic heart, in both atrial and ventricular myocytes, but are absent or much reduced in postnatal ventricular myocytes. However, ICaT is seen in many pathological conditions, but its mechanisms of re-expression are poorly
Regulation of ICaT expression
Several studies have now been reported (Table 2) concerning the effectors/mechanisms involved in regulation of the expression of cardiac T-type channels following the pioneering study of Xu and Best [13] describing that adult rat atrial myocytes treated with growth hormone from secreting tumors had a threefold increase in ICaT density. A secondary effect of increased levels of insulin growth factor 1, IGF-I was also considered in this study. Indeed physiological concentrations of IGF-I caused
Role of ICaT in the control of electrical activity, pacemaking and arrhythmia
The low threshold activation potential of T-type channels makes them likely candidates to provide an inward depolarizing current during the slow diastolic depolarization and contribute to cell automaticity. After the initial suggestion [2] and modeling [91] of a role for ICaT in pacemaking activity, its contribution was soon reported in adult rabbit sinus node using pharmacological tools, Ni2+ and tetramethrin [38], [92]. Indeed, ICaT has been found in all cardiac tissues showing automaticity (
Excitation-contraction coupling and secretion
Ca2+ entry through the L-type Ca2+ channels is considered to play a major role in cardiac myocytes as a trigger for Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR). Additional trigger mechanisms have been proposed, including Ca2+ entry via the reverse mode of Na+–Ca2+ exchanger during very strong depolarizations or as a consequence of subsarcolemmal accumulation of Na+ during activation of the Na+ current. There is no sound evidence for a charge-coupled (or voltage-gated)
Concluding remarks
Understanding the role of the T-type Ca2+ current and consequences of its variations during various physiopathological conditions requires that the investigations be performed in the most reliable and reproducible experimental conditions. The absence of ICaT in some cells of some species made difficult to ascribe a uniform role to this current in cardiomyocytes. It is worth interest whether aggressive enzymatic treatments and cell conservation methods or the use of intra- or extracellular
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2018, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :In the myocardium, T-type channels are expressed only during development and the perinatal period, but are absent in adult rats [11,12]. Interestingly, they can be re-expressed in adult cardiomyocytes in certain pathological conditions [13–15], although the mechanisms involved in this re-expression are not completely known [16]. Neonatal rat ventricular myocytes (NRVM) express CaV3.1 (α1G) and CaV3.2 (α1H) T-type Ca2+ channels [17,18], encoded by the Cacna1g and Cacna1h genes, respectively.