Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 283, Issue 3, Pages C941-C949Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00004.2002
Keywords
dihydropyridine receptor; excitation-contraction coupling; calcium channels; calcium transients; skeletal muscle
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Funding
- NIDDK NIH HHS [T32 DK-07739-02] Funding Source: Medline
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The skeletal muscle L-type calcium channel or dihydropyridine receptor (DHPR) plays an integral role in excitation-contraction (E-C) coupling. Its activation initiates three sequential events: charge movement (Q(r)), calcium release, and calcium current (I-Ca,I-L). This relationship suggests that changes in Q(r) might affect release and I-Ca,I-L. Here we studied the effect of gabapentin (GBP) on the three events generated by DHPRs in skeletal myotubes in culture. GBP specifically binds to the alpha(2)/delta(1) subunit of the brain and skeletal muscle DHPR. Myotubes were stimulated with a protocol that included a depolarizing prepulse to inactivate voltage-dependent proteins other than DHPRs. Gabapentin (50 muM) significantly increased Q(r) while decreasing the rate of rise of calcium transients. Gabapentin also reduced the maximum amplitude of the I-Ca,I-L (as we previously reported) without modifying the kinetics of activation. Exposure of GBP-treated myotubes to 10 muM nifedipine prevented the increase of Q(r) promoted by this drug, indicating that the extra charge recorded originated from DHPRs. Our data suggest that GBP dissociates the functions of the DHPR from the initial voltage-sensing step and implicates a role for the alpha(2)/delta(1) subunit in E-C coupling.
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