Another trigger for the heartbeat.

Abstract

Once upon a time, excitation-contraction (E-C) coupling in the heart was beginning to look simple. Calcium ions are accumulated in the sarcoplasmic reticulum (SR) and then released through Ca2+ channels (the ryanodine receptor or RyR) into the cytoplasm to activate contraction. The probability that the RyRs open is increased by cytoplasmic Ca2+. The increase of calcium ions required to trigger the opening of the RyRs is provided by the surface membrane L-type Ca2+ current. The overall process is referred to as calcium-induced calcium release (CICR). Much of the original work in this field was carried out by Fabiato (e.g. Fabiato, 1985). The simple story that the sarcolemmal Ca2+ current is the only trigger has been slightly confused by the suggestion that Ca2+ ions entering the cell on the Na+-Ca2+ exchanger (Leblanc & Hume, 1990) may also trigger the opening of the RyR. However, recent work has suggested that, for a given Ca2+ influx, the Na+-Ca2+ exchanger may be less efficient than the L-type Ca2+ trigger at promoting Ca2+ release from the SR (Sipido et al. 1997). This may reflect the fact that the L-type channel is situated closer to the RyR than is the Na+-Ca2+ exchanger. A radically different model of excitation-contraction coupling in the heart was proposed by Ferrier & Howlett (1995). They found that depolarization could still produce Ca2+ release from the SR even in the absence of measurable Ca2+ entry into the cell. In a paper in this issue of The Journal of Physiology this group have followed up their work and demonstrated that this mechanism requires a cAMP-dependent phosphorylation (Ferrier et al. 1998). The major problem involved in studying this voltage-dependent release mechanism is the problem of ensuring that Ca2+ entry into the cell has been adequately inhibited. There is always the possibility that an undetectably small entry of Ca2+ ions into the cell can produce significant release of Ca2+ from the SR, particularly under conditions when the SR Ca2+ content may have been increased by the presence of cAMP. Ferrier et al. (1998) have addressed this possibility by measuring the relationship between Ca2+ current and contraction and showing that, under conditions when the voltage-sensitive release mechanism appears to operate, the magnitude of contraction (and therefore presumably of the Ca2+ release) is too large to be accounted for by residual Ca2+ current. The evidence that Ca2+ entry does not contribute to Ca2+ release from the SR depends on pharmacological inhibition of known Ca2+ entry mechanisms as contraction is abolished in a Ca2+-free solution (Ferrier & Howlett, 1995). In our opinion, the evidence for a voltage-dependent Ca2+ release from the SR would be much stronger if conditions could be devised whereby the mechanism persisted in the absence of external Ca2+. Future work in this area will have to address several questions. (1) It is unclear what the structural basis of the voltage-activated release is. Voltage-activated release has long been known to be the mechanism of E-C coupling in skeletal muscle. In skeletal muscle the arrangement of the SR RyR and the sarcolemmal dihydropiridine (DHP) receptor has the regularity to be expected for this mechanism. In cardiac muscle, however, the linkage is less apparent (Sun et al. 1995). It is also worth noting that when the cardiac isoform of the DHP receptor is expressed in myotubes the resulting pattern of E-C coupling appears similar to that normally seen in cardiac muscle inasmuch as themagnitude of the Ca2+ transient parallels that of the Ca2+ current rather than simply increasing with depolarization. In contrast, if the skeletal isoform is expressed contraction increases monotonically with depolarization as is normally observed in skeletal muscle (Garcia et al. 1994). Although these results were obtained under very different conditions from those of Ferrier et al. (1998) the two sets of observations are not immediately reconcilable with a common model. (2) Thought has be to be given to how the voltage-activated mechanism might be regulated. If this mechanism is stimulated then there will be an initial increase of Ca2+ release from the SR This, however, will result in a decrease of SR Ca2+ content until Ca2+ release and contraction return to control levels (Eisner et al. 1998; Trafford et al. 1998). In contrast CICR provides a simple method of regulation: an increase of the L-type Ca2+ current not only stimulates Ca2+ release from the SR but also maintains the cell and SR Ca2+ content. While the problem of regulating the voltage-gated mechanism could be overcome by regulating cellular Ca2+ balance in parallel, it is less simple than the regulation of CICR. (3) It is likely that, even if Ca2+ release is initiated by a voltage-dependent mechanism, the resulting Ca2+ release from the SR will trigger further Ca2+ release by a CICR mechanism. This will provide a challenge to studying the properties of the putative voltage-sensitive mechanism as distinct from CICR. Finally, it has recently been reported that the application of two chemically distinct inotropic interventions (phosphorylation and cardiac glycosides) can transform cardiac TTX-sensitive Na+ channels into a form in which they allow conduct of Ca2+ into the cell and thereby trigger Ca2+ release from the SR (Santana et al. 1998). This provides yet another mechanism to account for phosphorylation stimulating SR Ca2+ release. Perhaps the real puzzle which must be solved before SR Ca2+ release can live ‘happily ever after’ is not so much what triggers Ca2+ release from the SR but what stops it happening?