A hot spot for the interaction of gating modifier toxins with voltage-dependent ion channels.
The gating modifier toxins are a large family of protein toxins that modify either activation or inactivation of voltage-gated ion channels. omega-Aga-IVA is a gating modifier toxin from spider venom that inhibits voltage-gated Ca(2+) channels by shifting activation to more depolarized voltages. We identified two Glu residues near the COOH-terminal edge of S3 in the alpha(1A) Ca(2+) 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 Ca(2+) channel had no significant effect on inhibition by omega-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 omega-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.
Winterfield
J R
JR
Molecular Physiology and Biophysics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Swartz
K J
KJ
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D005973:Glutamine / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011817:Rabbits; D051381:Rats; D013111:Spider Venoms / Q000494:pharmacology*; D020867:omega-Agatoxin IVA / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018076:DNA, Complementary; D013111:Spider Venoms; D020867:omega-Agatoxin IVA; D005973:Glutamine