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Skeletal muscle L-type Ca²⁺ current modulation in 1-deficient and wildtype murine myotubes by the 1 subunit and cAMP

Brigitte Held, Doris Freise, Marc Freichel, Markus Hoth * and Veit Flockerzi

Modulation of the steady-state inactivation and current amplitude by the 1 subunit of the murine skeletal muscle L-type Ca²⁺ channel were investigated using the whole-cell patch-clamp technique. Transient expression of the 1 subunit, but not of the 2 (stargazin) protein, in primary cultured myotubes from 1-deficient mice shifted the steady-state inactivation approximately -15 mV, thereby restoring wildtype (WT) steady-state inactivation and current amplitude. The increased Ca²⁺ current amplitude in 1-deficient cells was abolished in myotubes from animals of 4 weeks and older whereas the positive shift in steady-state inactivation was independent of mouse age. Raising intracellular cAMP levels using the membrane-permeant analogue 8-Br-cAMP led to an increase in Ca²⁺ current amplitude in WT cells to the level in 1-deficient myotubes. There was no effect on the current amplitude in 1-deficient cells or on the steady-state inactivation in either genotype. Rp-cAMPS, a competitive inhibitor of cAMP-dependent protein kinase, had no effect on the WT Ca²⁺ current amplitude and steady-state inactivation, but diminished the current amplitude in 1-deficient myotubes without affecting the steady-state inactivation in these cells. These data show that the increased Ca²⁺ influx in myotubes lacking the 1 subunit, due to right-shifted steady-state inactivation and increased L-type Ca²⁺ current amplitude, is determined by the 1 subunit. The effect on current amplitude depends on the age of the mice and its cAMP-dependent modulation appears to be controlled by the 1 subunit.

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