Dissociation of charge movement from calcium release and calcium current in skeletal myotubes by gabapentin.
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,L)). This relationship suggests that changes in Q(r) might affect release and I(Ca,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 microM) significantly increased Q(r) while decreasing the rate of rise of calcium transients. Gabapentin also reduced the maximum amplitude of the I(Ca,L) (as we previously reported) without modifying the kinetics of activation. Exposure of GBP-treated myotubes to 10 microM 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.
Alden
Kris J
KJ
Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine, 60607, USA.
García
Jesús
J
D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003509:Cyclohexanecarboxylic Acids; D004558:Electric Stimulation / Q000379:methods; D000077206:Gabapentin; D017136:Ion Transport / Q000187:drug effects; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D003509:Cyclohexanecarboxylic Acids; D021122:Protein Subunits; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009543:Nifedipine; D002118:Calcium