Excitation Contraction Coupling in Cardiac Muscle: Is there a Purely Voltage-dependent Component?

It is well established that excitation contraction (EC) coupling in cardiac myocytes is mediated by the entry of calcium ions (Ca 2 ) from the bathing medium into the cell cytoplasm (Fabiato, 1985), which then triggers calcium-induced calcium release (CICR) from the sarcoplasmic reticulum (SR). More recently, it was proposed that a second, quite separate, EC-coupling process, mediated by an effect of membrane potential per se on SR Ca 2 release, also operates in cardiac myocytes (Ferrier and Howlett, 1995; Hobai et al., 1997; Howlett and Ferrier, 1997; Howlett et al., 1998, 1999; Ferrier et al., 1998, 2000; Mason and Ferrier, 1999; Zhu and Ferrier, 2000; for review see Ferrier and Howlett, 2001). Although a substantial body of diverse experimental observations has been reported in support of this voltagesensitive release mechanism (VSRM; Ferrier and Howlett, 2001), it remains highly controversial (Nabauer et al., 1989; Wier and Balke, 1999; Piacentino et al., 2000; Sipido, 2003; Trafford and Eisner, 2003). One reason for reservations regarding VSRM is that it is said to be observable only under very restricted conditions: very negative holding potentials, temperatures near 37 C, a fully loaded SR, and, for internally dialyzed cells, in the presence of agents that promote protein kinase A (PKA)-mediated phosphorylation. These conditions all increase either L-type Ca 2 currents (I Ca(L) ) or SR Ca 2 release. Hence, conditions purported to demonstrate VSRM could, instead, just be enhancing CICR. A further problem is that whereas nominally Ca 2 -free bathing media fully abolish contraction, contraction is restored with as little as 50 M external Ca 2 (Ferrier and Howlett, 1995). Ferrier and Howlett (1995) have taken this result to indicate that a small amount of external Ca 2 is required as a kind of cofactor for VSRM, as opposed to actual Ca 2 entry. However, the observation could equally well indicate that only little Ca 2 entry is needed to trigger SR Ca 2