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Properties and Functional Roles of T-Type Ca Channels in Cardiac

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Properties and Functional Roles of T-Type Ca Channels in Cardiac J Pharmacol Sci 99, 197 – 204 (2005) Journal of Pharmacological Sciences ©2005 The Japanese Pharmacological Society Forum Minireview Pathophysiological Significance of T-type Ca2+ Channels: Properties and Functional Roles of T-type Ca2+ Channels in Cardiac Pacemaking Kyoichi Ono1,* and Toshihiko Iijima1 1Department of Pharmacology, Akita University School of Medicine, Akita 010-8543, Japan Received August 11, 2005; Accepted October 12, 2005 Abstract. Calcium channels are essential for excitation-contraction coupling and pacemaker activity in cardiac myocytes. While L-type Ca2+ channels (LCC) have been extensively studied, functional roles of T-type channels (TCC) in native cardiac myocytes are still debatable. TCC are activated at more negative membrane potentials than LCC and therefore facilitate slow diastolic depolarization in sinoatrial node cells. Recent studies showed that selective inhibition of TCC produced a marked slowing of the pacemaker rhythm, indicating that contribution of TCC to cardiac automaticity was relatively larger than what had been speculated in previous studies. To re-evaluate TCC, we measured current density and kinetics of TCC in sinoatrial node cells of various mammalian species. Current density of TCC was larger in mice and guinea pigs than in rabbit and porcine sinoatrial node cells. Interestingly, few or no obvious TCC were recorded in porcine sinoatrial node cells. Furthermore, it was demonstrated that TCC could be enhanced by several vasoactive substances, thereby increasing spontaneous firing rate of sinoatrial node cells. TCC may, at least in part, account for different heart rates among various mammalian species. In addition, TCC might be involved in physiological and/or pathophysio- logical modulations of the heart rate. Keywords: T-type Ca2+ channel, sinoatrial node, cardiac automaticity, pacemaker activity Introduction provoke pacemaker depolarization. Furthermore, lack of sensitivity to β-adrenergic simulation excludes the T-type Ca2+ channels (TCC) were originally called possibility that TCC may, at least, contribute to an low-voltage-activated (LVA) or transient-type Ca2+ increase in heart rate during sympathetic nerve stimula- channels because they can be activated by small depolar- tion. On the other hand, recent studies showed that izations of the plasma membrane and are inactivated selective inhibition of TCC produced a marked slowing more quickly than other voltage-dependent Ca2+ chan- of the pacemaker rhythm (2, 3). In addition, it was nels. In the heart, L-type Ca2+ channels (LCC) are most shown that in cat atrial pacemaker cells, Ca2+ influx abundant, and are responsible for Ca2+ entry into cells through TCC triggered the release of Ca2+ from sarco- that trigger contraction; whereas TCC are most prevalent plasmic reticulum (SR), which in turn activated a in the conduction system and are probably involved in forward mode of the Na+/Ca2+ exchanger (4). The result- automaticity (1). However, quantitative contribution ing inward current promoted pacemaker depolarization. of TCC to heart automaticity is still not clear. Some Thus, contribution of TCC to cardiac automaticity seems studies showed that blockage of TCC using Ni2+ slowed relatively larger than that speculated in previous studies. firing frequency of sinoatrial node (SAN) cells only In this review, we re-evaluate TCC on the basis of slightly (1). Indeed, the transient nature of TCC makes it current density, kinetics, and physiological modulation difficult to carry inward currents, which is sufficient to in various mammalian species. *Corresponding author. FAX: +81-18-836-2603 E-mail: [email protected] 197 198 K Ono and T Iijima Electrophysiological properties of sinoatrial TCC and determine most of the channel characteristics such as single channel amplitude, voltage-dependent acti- It is well known that ICaT differs from ICaL on the basis vation, and sensitivity to organic calcium channel of its low-voltage activation range and rapid inactiva- blockers. Ten genes encoding pore-forming α1 subunits tion. The activation range of ICaT is more negative than have been reported. Among these α1 subunits, Cav3.1 that of ICaL, and it overlaps the pacemaker potential. (α1G), Cav3.2 (α1H), and Cav3.3 (α1I) are thought to form Threshold for activation of ICaT is around −60 mV, and ICaT (8, 9) (Fig. 2). Their deduced amino acid sequences ICaT is fully activated at about −10 mV. Inactivation showed a similar four-repeat structure to that found in 2+ + occurs more rapidly than with ICaL. ICaT starts to inacti- high-voltage-activated Ca channels and Na channels, vate at −90 mV and is completely inactivated at −40 mV. indicating that they were evolutionarily related. Because of these characteristics, ICaT can be electro- Although mRNAs for all three Cav3 subtypes are physiologically distinguished from ICaL by changing the expressed in brain, they vary in terms of their peripheral holding potential (Fig. 1A). Another way to discriminate expression, and only Cav3.1 and Cav3.2 are expressed in 2+ ICaT from ICaL is to use Ni as an ICaT blocker since native the heart. Cav3.1 mRNA expression is 30-fold greater in 2+ ICaT is more sensitive to Ni than ICaL (Fig. 1B). SAN cells of the mouse than in atrial cells (10). Cav3.2 is Figure 1C shows a family of ICaL and ICaT obtained also present, although only in moderate amounts (10). from guinea-pig SAN cells using the electrophysio- logical isolation method. It was evident that ICaT started to activate at around −60 mV and inactivated more rapidly than ICaL. Activation range of ICaT overlapped the pacemaker potential of SAN (Fig. 1D), whereas ICaL contributed to the upstroke of the action potential. ICaT was recorded in SAN cells of various species (mouse, rat, rabbit, and guinea pig) (1, 5 – 7). Molecular basis of TCC Voltage-dependent Ca2+ channels are electrophysio- logically and pharmacologically classified into five groups (P/Q, N, L, R, and T) (Fig. 2). Biophysically, α γ β 2+ calcium channels are composed of four subunits, 1, , , Fig. 2. Evolutionary tree of voltage-gated Ca channels. Modified and α2δ. The α1 subunits are the pore-forming subunits, from Ref. 8 with permission. Fig. 1. Separation of ICaT from ICaL in native sinoatrial node (SAN) cells. A: Superimposed current traces were obtained from guinea-pig SAN cells by depolarization from either −40 or −90 mV to 0 mV. Pulse duration was 300 ms. External and pipette solutions were Na+- and K+- free solutions. The bottom trace shows the differ- ence current. B: Superimposed current traces were obtained in the absence and presence of 50 µM Ni2+. Holding potential was −90 mV, and test potential was −40 mV. The lower trace shows the difference current. C: Current families of ICaT (upper traces) and ICaL (lower traces) were obtained by the electrophysiological isolation method shown in panel A. D: Spontaneous action potential of SAN and activation thresholds for ICaT and ICaL. Note that activation range of ICaT overlaps the pacemaker potential. T-type Ca2+ Channels in Cardiac Pacemaking 199 Table 1. Comparison of electrophysiological and pharmacological parameters between cloned and native ICa Cloned T-type channels Native ICa Cav3.1 (α1G)Cav3.2 (α1H)Cav3.3 (α1I) ICaT ICaL Brain, ovary, Kidney, liver, adrenal Tissue expression placenta, heart cortex, brain, heart Brain (Sinoatrial node cells) (sinoatrial node) (sinoatrial node) Electrophysiology Threshold −70 −70 −70 −60 −30 Peak −30 −30 −30 −20 – −30 −10 – +10 τ, activation (at −10 mV, ms) 1 2 7 several ms several ms τ, inactivation (at −10 mV, ms) 11 16 69 approx. 10 approx. 100 V1/2 for inactivation −72 −72 −72 −75 −25 Conductance, pS 7.5 9 11 8.5 16 Pharmacology Nickel (IC50, mM) 250 12 216 approx. 10 >100 Mibefradil (IC50, µM) 0.2 – 1.2 0.1 – 1.1 1.5 1.5 n/a Efonidipine (IC50, µM) 0.4 0.48 n/a Amlodipine >10 0.075 References 8 8 8 1, 3 1 n/a: not analyzed. Electrophysiological activities of recombinant Cav3 channels are very similar to native ICaT; and they can be differentiated from ICaL by their activation at lower voltages, faster inactivation, slower deactivation, and 2+ smaller conductance of Ba (11) (Table 1). The Cav3.1 and Cav3.2 subtypes can be differentiated by their kinetics and sensitivity to block Ni2+. These findings may indicate that ICaT is largely derived from Cav3.2 in SAN cells. Species differences of TCC density Amplitude of ICaT was compared among various mammalian species. In mouse SAN cells, substantial amplitude of ICaT could be detected in all cells examined, and peak amplitude was larger than that of ICaL in the current-voltage relation (7). The relative size of ICaT became small in guinea-pig SAN cells (Fig. 3A) and was reduced further in rabbit SAN cells (1). It was interesting Fig. 3. Whole-cell Ca2+ current carried via LCC and TCC in sinoatrial node (SAN) cells. A: Guinea-pig SAN cells. Aa: Currents to note that ICaT was virtually absent in porcine SAN cells obtained from a holding potential of either −80 or −40 mV are (Fig. 3B). These findings indicated significant species superimposed for each test potential. Test potential is indicated above differences in ICaT expression. A previous study reported each pair of currents. Ab: Current-voltage relationship for peak that ICaT was absent in adult human atrial (12) and amplitude of ICaL (open circles) and ICaT (filled circles). B: Porcine ventricular cells. In large animals (i.e., pigs and SAN cells. Same explanation as in panel A. Note that no obvious 2+ I ICaT is detected in porcine SAN cells. Modified from Ref. 13 with humans), Ca may be exclusively carried via CaL, and permission. not ICaT. It is well known that heart rate is different among various mammalian species, that is, it is very fast in is slower in large animals including humans, pigs, and so small animals such as mice, rats, and guinea pigs, and it on (13 – 15).
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