Voltage-dependent potentiation of L-type Ca2+ channels due to phosphorylation by cAMP-dependent protein kinase

The force of contraction of motor units in skeletal muscle is graded by changing the discharge rate of motor neurons, and cytosolic calcium transients are similarly increased. During single twitches, contraction is not dependent on extracellular calcium, and L-type Ca2+ channels may only function as voltage sensors for initiating Ca2+ release from the sarcoplasmic reticulum. In contrast, forceful tetanic contractions triggered by action potentials at high frequency (20 to 200 Hz) are dependent on extracellular Ca2+ concentration and sensitive to L-type Ca2+ channel antagonists, but the mechanism of regulation of contractile force is unknown. Here we report a large, voltage- and frequency-dependent potentiation of skeletal muscle L-type Ca2+ currents by trains of high-frequency depolarizing prepulses, which is caused by a shift in the voltage-dependence of channel activation to more negative membrane potentials and requires phosphorylation by cyclic AMP-dependent protein kinase in a voltage-dependent manner. This potentiation would substantially increase Ca2+ influx and contractile force in skeletal muscle fibres in response to tetanic stimuli.