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Original Article |
Correspondence to: Kenton J. Swartz, Molecular Physiology and Biophysics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 36, Room 2C19, 36 Convent Drive, MSC 4066, Bethesda, MD 20892. Fax:(301) 435-5666 E-mail:swartzk{at}ninds.nih.gov.
The gating modifier toxins are a large family of protein toxins that modify either activation or inactivation of voltage-gated ion channels. 
-Aga-IVA is a gating modifier toxin from spider venom that inhibits voltage-gated Ca2+ channels by shifting activation to more depolarized voltages. We identified two Glu residues near the COOH-terminal edge of S3 in the 
1A Ca2+ channel (one in repeat I and the other in repeat IV) that align with Glu residues previously implicated in forming the binding sites for gating modifier toxins on K+ and Na+ channels. We found that mutation of the Glu residue in repeat I of the Ca2+ channel had no significant effect on inhibition by -Aga-IVA, whereas the equivalent mutation of the Glu in repeat IV disrupted inhibition by the toxin. These results suggest that the COOH-terminal end of S3 within repeat IV contributes to forming a receptor for -Aga-IVA. The strong predictive value of previous mapping studies for K+ and Na+ channel toxins argues for a conserved binding motif for gating modifier toxins within the voltage-sensing domains of voltage-gated ion channels.
Key Words: calcium channels, mutagenesis, agatoxin, voltage-sensing domain
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