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A novel Conus snail polypeptide causes excitotoxicity by blocking desensitization of AMPA receptors.


ABSTRACT: 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.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.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.

SUBMITTER: Walker CS 

PROVIDER: S-EPMC2722447 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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A novel Conus snail polypeptide causes excitotoxicity by blocking desensitization of AMPA receptors.

Walker Craig S CS   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  

Current biology : CB 20090528 11


<h4>Background</h4>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 dese  ...[more]

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