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Voltage-dependent Ca²⁺ release from the SR of feline ventricular myocytes is explained by Ca²⁺-induced Ca²⁺ release

Valentino Piacentino III, Konstantina Dipla, John P. Gaughan and Steven R. Houser

1. Direct voltage-gated (voltage-dependent Ca²⁺ release, VDCR) and Ca²⁺ influx-gated (Ca²⁺-induced Ca²⁺ release, CICR) sarcoplasmic reticulum (SR) Ca²⁺ release were studied in feline ventricular myocytes. The voltage-contraction relationship predicted by the VDCR hypothesis is sigmoidal with large contractions at potentials near the Ca²⁺ equilibrium potential (E_Ca). The relationship predicted by the CICR hypothesis is bell-shaped with no contraction at E_Ca.

2. The voltage dependence of contraction was measured in ventricular myocytes at physiological temperature (37 °C), resting membrane potential and physiological [K⁺]. Experiments were performed with cyclic adenosine 3',5'-monophosphate (cAMP) in the pipette or in the presence of the -adrenergic agonist isoproterenol (isoprenaline; ISO).

3. The voltage-contraction relationship was bell-shaped in Na⁺-free solutions (to eliminate the Na⁺ current and Na⁺-Ca²⁺ exchange, NCX) but the relationship was broader than the L-type Ca²⁺ current (I_Ca,L)-voltage relationship.

4. Contractions induced with voltage steps from normal resting potentials to -40 mV are thought to represent VDCR rather than CICR. We found that cAMP and ISO shifted the voltage dependence of I_Ca,L activation to more negative potentials so that I_Ca,L was always present with steps to -40 mV. I_Ca,L at -40 mV inactivated when the holding potential was decreased (V_½ = -57·8 ± 0·49 mV).

5. ISO increased inward current, SR Ca²⁺ load and contraction in physiological [Na⁺] and a broad bell-shaped voltage-contraction relationship was observed. Inhibition of reverse-mode NCX, decreasing I_Ca,L and decreasing SR Ca²⁺ loading all decreased contractions at strongly positive potentials near E_Ca.

6. The voltage-contraction relationship in 200 µM cadmium (Cd²⁺) was bell-shaped, supporting a role of I_Ca,L rather than VDCR.

7. All results could be accounted for by the CICR hypothesis, and many results exclude the VDCR hypothesis.

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