The term excitation-coupled Ca 2+entry (ECCE) designates the entry of extracellular Ca 2+ into skeletal muscle cells, which occurs in response to prolonged depolarization or pulse trains and depends on the presence of both the 1,4-dihydropyridine receptor (DHPR) in the plasma membrane and the type 1 ryanodine receptor in the sarcoplasmic reticulum (SR) membrane. The ECCE pathway is blocked by pharmacological agents that also block store-operated Ca 2+ entry, is inhibited by dantrolene, is relatively insensitive to the DHP antagonist nifedipine (1 μ M), and is permeable to Mn 2+ . Here, we have examined the effects of these agents on the L-type Ca 2+ current conducted via the DHPR. We found that the nonspecifi c cation channel antagonists (2-APB, SKF 96356, La 3+ , and Gd 3+ ) and dantrolene all inhibited the L-type Ca 2+ current. In addition, complete ( > 97%) block of the L-type current required concentrations of nifedipine > 10 μ M. Like ECCE, the L-type Ca 2+ channel displays permeability to Mn 2+ in the absence of external Ca 2+ and produces a Ca 2+ current that persists during prolonged ( ̃ 10-second) depolarization. This current appears to contribute to the Ca 2+ transient observed during prolonged KCl depolarization of intact myotubes because (1) the transients in normal myotubes decayed more rapidly in the absence of external Ca 2+ ; (2) the transients in dysgenic myotubes expressing SkEIIIK (a DHPR α 1S pore mutant thought to conduct only monovalent cations) had a time course like that of normal myotubes in Ca 2+-free solution and were unaffected by Ca 2+ removal; and (3) after block of SR Ca 2+ release by 200 μ M ryanodine, normal myotubes still displayed a large Ca 2+ transient, whereas no transient was detectable in SkEIIIK-expressing dysgenic myotubes. Collectively, these results indicate that the skeletal muscle L-type channel is a major contributor to the Ca 2+ entry attributed to ECCE.
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