QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.108.045153v1 74/3/904    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mich, P. M. Articles by Horne, W. A. PubMed PubMed Citation Articles by Mich, P. M. Articles by Horne, W. A.

Alternative Splicing of the Ca²⁺ Channel β4 Subunit Confers Specificity for Gabapentin Inhibition of Ca_v2.1 Trafficking

Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado (P.M.M.); and Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York (W.A.H.)

Gabapentin is well established as an effective treatment for neuropathic pain; however, little is known about its mechanism of action. It binds with high affinity to Ca²⁺ channel 2 subunits that are expressed in dorsal root ganglia. Mutation of a single 2 amino acid, R217A, eliminates both gabapentin binding and analgesic efficacy. Gabapentin does not seem to have direct Ca²⁺ channel blocking properties but does affect overall levels of Ca²⁺ channel surface expression in some circumstances. In this report, we examined gabapentin effects on trafficking and voltage-dependent gating properties of recombinant Ca_v2.1 Ca²⁺ channel complexes transiently expressed in Xenopus laevis oocytes. We also determined electrophysiologically whether gabapentin causes displacement of β subunits from Ca_v2.1 complexes. Our principal findings are as follows: 1) gabapentin inhibits trafficking of recombinant Ca_v2.1 Ca²⁺ channels in X. laevis oocytes; 2) gabapentin inhibition occurs in the presence of the Ca²⁺ channel β4a subunit but not in the presence of β4b; 3) gabapentin does not affect Ca_v2.1 voltage-dependent gating parameters; 4) inhibition of Ca_v2.1trafficking is highly dependent on β-subunit concentration; and 5) gabapentin inhibition of Ca_v2.1 trafficking can be reversed by the 2 R217A mutation. Overall, our results suggest that gabapentin reduces the number of β4a-bound Ca_v2.1 complexes that are successfully trafficked to the plasma membrane. This mechanism may help to explain why gabapentin is both effective and selective in the treatment of neuropathic pain states that involve up-regulation of 2 subunits.

Address correspondence to: William A. Horne, T8 016A, Box 34, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850. E-mail: wah27{at}cornell.edu