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J. Biol. Chem., Vol. 275, Issue 28, 21309-21316, July 14, 2000

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The Spider Toxin -Aga IIIA Defines a High Affinity Site on Neuronal High Voltage-activated Calcium Channels^*

Lizhen Yan and Michael E. Adams^§

From the Environmental Toxicology Graduate Program and Departments of Entomology and Neuroscience, University of California, Riverside, California 92521

The spider toxin -agatoxin IIIA (-Aga-IIIA) is a potent inhibitor of high voltage-activated calcium currents in the mammalian brain. To establish the biochemical parameters governing its action, we radiolabeled the toxin and examined its binding to native and recombinant calcium channels. In experiments with purified rat synaptosomal membranes, both kinetic and equilibrium data demonstrate one-to-one binding of -Aga-IIIA to a single population of high affinity sites, with K_d = ~9 pM and B_max = ~1.4 pmol/mg protein. Partial inhibition of -Aga-IIIA binding by -conotoxins GVIA, MVIIA, and MVIIC identifies N and P/Q channels as components of this population. -Aga-IIIA binds to recombinant _1B and _1E calcium channels with a similar high affinity (K_d = ~5-9 pM) in apparent one-to-one fashion. Results from recombinant _1B binding experiments demonstrate virtually identical B_max values for -Aga-IIIA and -conotoxin MVIIA, providing further evidence for a one-to-one stoichiometry of agatoxin binding to calcium channels. The combined evidence suggests that -Aga-IIIA defines a unique, high affinity binding site on N-, P/Q-, and R-type calcium channels.

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