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The α2δ Auxiliary Subunit Reduces Affinity of ω-Conotoxins for Recombinant N-type (Cav2.2) Calcium Channels*

Jorgen A. Mould,T. Yasuda,C. Schroeder,Aaron M. Beedle,C. Doering,G. Zamponi,David John Adams,R. Lewis

Published 2004 in Journal of Biological Chemistry

ABSTRACT

The ω-conotoxins from fish-hunting cone snails are potent inhibitors of voltage-gated calcium channels. The ω-conotoxins MVIIA and CVID are selective N-type calcium channel inhibitors with potential in the treatment of chronic pain. The β and α2δ-1 auxiliary subunits influence the expression and characteristics of the α1B subunit of N-type channels and are differentially regulated in disease states, including pain. In this study, we examined the influence of these auxiliary subunits on the ability of the ω-conotoxins GVIA, MVIIA, CVID and analogues to inhibit peripheral and central forms of the rat N-type channels. Although the β3 subunit had little influence on the on- and off-rates of ω-conotoxins, coexpression of α2δ with α1B significantly reduced on-rates and equilibrium inhibition at both the central and peripheral isoforms of the N-type channels. The α2δ also enhanced the selectivity of MVIIA, but not CVID, for the central isoform. Similar but less pronounced trends were also observed for N-type channels expressed in human embryonic kidney cells. The influence of α2δ was not affected by oocyte deglycosylation. The extent of recovery from the ω-conotoxin block was least for GVIA, intermediate for MVIIA, and almost complete for CVID. Application of a hyperpolarizing holding potential (-120 mV) did not significantly enhance the extent of CVID recovery. Interestingly, [R10K]MVIIA and [O10K]GVIA had greater recovery from the block, whereas [K10R]CVID had reduced recovery from the block, indicating that position 10 had an important influence on the extent of ω-conotoxin reversibility. Recovery from CVID block was reduced in the presence of α2δ in human embryonic kidney cells and in oocytes expressing α1B-b. These results may have implications for the antinociceptive properties of ω-conotoxins, given that the α2δ subunit is up-regulated in certain pain states.

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