Role of T-type Ca²⁺ channels in the heart

Abstract

After the first demonstration 30 years ago that Ca²⁺ could permeate through two different channels, the occurrence and role of T-type Ca²⁺ current, I_CaT have been the matter of hundreds of publications, including the two 1985’ reports in various cardiac tissues and species. Except for its specific biophysical characteristics, I_CaT is no longer so easily distinguished from the L-type Ca²⁺ current, I_CaL, since it is also sensitive to multiple compounds and various neuromediators including the β-adrenergic agonists. Changes in I_CaT occur during development, so that while it is recorded in all embryonic and neonatal cells investigated, I_CaT has been reported in adult ventricular cells of only few species in control. However, under various pathological conditions, I_CaT is often recorded at some phases of remodelling at least in some localized area and one or more of the three channel proteins, Cav3.1–3.3 are clearly re-expressed under the influence of IGF-1, endothelin, and angiotensin II. I_CaT contributes to the control of electrical activity including pacemaker and arrhythmia. Furthermore I_CaT, and its low-depolarisation window current, participate in Ca²⁺ entry, so that I_CaT has been involved in the release of Ca²⁺ from internal stores, the Ca²⁺-induced Ca²⁺ release mechanism, although at much lower level than I_CaL. I_CaT contributes also to Ca²⁺-dependent hormonal secretion. This review further emphasizes the difficulties encountered in analysing this current.

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, I_CaT, following the nomenclature established by Tsien's group, while the “classical” Ca²⁺ current was denominated L-type (“long lasting”), I_CaL. 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 Ca_V3.1–3.3 (α_1G, α_1H and α_1I), two of which (Ca_V3.1 and Ca_V3.2) are expressed in the heart (see [6]).