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Which Ca²⁺ channels control cardiac E-C coupling?

Peter Lipp & Martin D. Bootman

During every heartbeat, an electrical action potential is transduced into the co-ordinated mechanical activity of each cardiac myocyte, a process generally referred to as excitation- contraction (E-C) coupling (for a review see Callewaert, 1992). The invading action potential depolarizes the sarcolemma and activates voltage-sensitive Ca²⁺ influx across the surface of each cell. This Ca²⁺ influx is amplified by a rapid transient Ca²⁺ release from channels (ryanodine receptors; RyRs) located on the sarcoplasmic reticulum (SR), via a process known as Ca²⁺-induced Ca²⁺ release (CICR). It is this increase of cytosolic Ca²⁺ (from resting concentrations of approximately 100 nM to 1 µM) that leads to contraction.

Although it is well established that Ca²⁺ influx through L-type voltage-sensitive channels is the predominant trigger for CICR under physiological conditions, the contribution of other Ca²⁺ channels/ Ca²⁺ influx mechanisms is unclear. In particular, the putative role of the T-type channels in cardiac E-C coupling is an open question. Evidence for T-type Ca²⁺ currents in cardiac myocytes has been presented by several groups (e.g. Nilius et al. 1985; Balke et al. 1992), thus substantiating the idea that these channels could participate in E-C coupling.

In a paper in this issue, Sipido et al. (1998) provide further evidence for the expression and function of T-type channels in guinea-pig cardiac myocytes. Essentially, they investigated whether (i) the T-type Ca²⁺ current is able to trigger CICR and (ii) its relative efficiency of evoking CICR in comparison with the L-type Ca²⁺ current. In order to record pure T- and L-type Ca²⁺ currents, Sipido et al. substituted all monovalent cations with impermeant species, such as tetraethylammonium (TEA). Under such conditions, depolarization of the sarcolemma from -90 to -50 mV (which is insufficient to activate L-type Ca²⁺ currents) triggered only the T-type Ca²⁺ current, giving a small, slowly rising cytosolic [Ca²⁺] increase.

By applying different pre-pulse protocols, Sipido et al. were able to show that Ca²⁺ influx through the T-type Ca²⁺ channels contributed only a minor portion of the total Ca²⁺ signals. Instead, they found that the major part of the Ca²⁺ transient originated from the SR via CICR, thus supporting a possible role for the T-type current in the E-C coupling process.

However, the situation is not so straightforward. Measurement of the inward current amplitude over a wide range of depolarizing voltages, revealed that the contribution of T-type channels was significant during small depolarizing steps, but became much less pronounced with increasing depolarizing steps, when L-type channels progressively activate. In fact, when the L-type current was fully activated, the T-type current was almost negligible. The significance of this is that during a 'physiological' action potential, CICR will largely be triggered by the L-type Ca²⁺ current, and not the T-type current.

In addition, Sipido et al. show that L-type and T-type Ca²⁺ currents display a different 'gain', in that L-type currents triggered more CICR than T-type currents of similar amplitude. The reason for the relatively poorer activation of CICR by T-type Ca²⁺ channels may be due to a spatial separation of the channels and RyRs. On the other hand, the L-type channels may be spatially closer, giving them a greater potential for functional coupling. Consistent with this model, L-type channel inactivation was increased with more substantial Ca²⁺ release from the SR, whereas T-type current inactivation was unaffected. This strongly suggests that RyRs have a priveleged access to L-type Ca²⁺ channels but not to T-type channels.

Since these data indicate that T-type currents are unlikely to trigger CICR significantly during an action potential, the question arises as to the function(s) of T-type Ca²⁺ channels. Potentially, they may act synergistically with the L-type currents to help trigger CICR. In addition, the T-type currents may help to maintain the SR Ca²⁺ load since blocking the current with Ni²⁺ did not immediately affect the action potential induced Ca²⁺ transients, but progressively caused them to decrease (Sipido et al. 1998).

In ventricular myocytes, several mechanisms for triggering CICR from the SR have been proposed, including a putative voltage-dependent Ca²⁺ release and Ca²⁺ influx via reverse-mode Na⁺-Ca²⁺ exchange or L- and T-type channels.

Since the roles of voltage-dependent Ca²⁺ release (see Hobai et al. 1997) and reverse-mode Na⁺- Ca²⁺ exchange are still debated, their relative contribution during an action potential is unclear. However, the data from Sipido et al. lend support to the idea that L-type Ca²⁺ currents are predominant, at least over T-type currents, during physiological stimulation.