A novel Conus snail polypeptide causes excitotoxicity by blocking desensitization of AMPA receptors.
BACKGROUND
Ionotropic glutamate receptors (iGluRs) are glutamate-gated ion channels that mediate excitatory neurotransmission in the central nervous system. Based on both molecular and pharmacological criteria, iGluRs have been divided into two major classes, the non-NMDA class, which includes both AMPA and kainate subtypes of receptors, and the NMDA class. One evolutionarily conserved feature of iGluRs is their desensitization in the continued presence of glutamate. Thus, when in a desensitized state, iGluRs can be bound to glutamate, yet the channel remains closed. However, the relevance of desensitization to nervous system function has remained enigmatic.


RESULTS
Here, we report the identification and characterization of a novel polypeptide (con-ikot-ikot) from the venom of a predatory marine snail Conus striatus that specifically disrupts the desensitization of AMPA receptors (AMPARs). The stoichiometry of con-ikot-ikot appears reminiscent of the proposed subunit organization of AMPARs, i.e., a dimer of dimers, suggesting that it acts as a molecular four-legged clamp that holds the AMPAR channel open. Application of con-ikot-ikot to hippocampal slices caused a large and rapid increase in resting AMPAR-mediated current leading to neuronal death.


CONCLUSIONS
Our findings provide insight into the mechanisms that regulate receptor desensitization and demonstrate that in the arms race between prey and predators, evolution has selected for a toxin that blocks AMPAR desensitization, thus revealing the fundamental importance of desensitization for regulating neural function.
Walker
Craig S
CS
Department of Biology, University of Utah, Salt Lake City, UT 84112-0840, USA.
Jensen
Stori
S
Ellison
Michael
M
Matta
Jose A
JA
Lee
Won Yong
WY
Imperial
Julita S
JS
Duclos
Nick
N
Brockie
Penelope J
PJ
Madsen
David M
DM
Isaac
John T R
JT
Olivera
Baldomero
B
Maricq
Andres V
AV
D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology; D001665:Binding Sites; D005591:Chemical Fractionation; D002851:Chromatography, High Pressure Liquid; D052078:Conus Snail / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D004553:Electric Conductivity; D006624:Hippocampus / Q000187:drug effects; D008978:Mollusk Venoms / Q000737:chemistry*; D009498:Neurotoxins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014981:Xenopus
D001581:Benzothiadiazines; D008978:Mollusk Venoms; D009498:Neurotoxins; D010455:Peptides; D018091:Receptors, AMPA; D011994:Recombinant Proteins; C004639:cyclothiazide