Phenylalkylamine L-type Ca²⁺ channel antagonists influence excitation-contraction coupling in frog skeletal muscle by shifting the steady state inactivation curve of the DHP receptor voltage sensor to more negative potentials (Erdmann and Lüttgau, J Physiol 1989). In a recent study of muscle fibers isolated from mice deficient in the [gamma]1 subunit of the DHP receptor, we demonstrated that this auxiliary protein exerts a similar effect on inactivation (Ursu et al., JGP 2004). This raises the possibility of a common modulatory mechanism. To investigate the question of how the [gamma]1 subunit influences drug action we studied steady state inactivation and the time course of recovery from inactivation of both cell membrane Ca²⁺ conductance and sarcoplasmic reticulum Ca²⁺ release flux in the presence of different concentrations of the phenylalkylamine drug (-)D888 (Devapamil). D888 induced a concentration-dependent shift of steady state inactivation to negative potentials and delayed recovery in a voltage-dependent manner. In [gamma]1 -/- muscle fibers exposed to 5 mM Devapamil, the voltages of half-maximal inactivation and recovery were close to the values in [gamma]1 +/+ fibers. In [gamma]1 +/+ fibers, D888 also caused a shift of the voltage dependences to more negative potentials indicating that [gamma]1 and D888 jointly promote stabilization of inactivation. [gamma]1 may serve a modulatory function as an endogenous Ca²⁺ antagonist.