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Kainate Receptors as a Target for the Anticonvulsant Perampanel

红藻氨酸受体作为抗惊厥药吡仑帕奈的靶点

基本信息

批准号：
10452382
负责人：
GEOFFREY T SWANSON
金额：
$ 23.07万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452382
关键词：
AMPA Receptors Adverse effects Amino Acids Analgesics Animal Model Animals Anticonvulsants Anxiety Behavioral Assay Binding Binding Sites Brain Brain region Chronic Clinical Complex Data Dose Elements Epilepsy Equilibrium Exploratory/Developmental Grant Family Functional disorder Generations Glutamate Receptor Hippocampal Mossy Fibers Hippocampus (Brain)Kainic Acid Receptors Knockout Mice Lead Mediator of activation protein Modeling Molecular Mus Neurons Outcome Pharmaceutical Preparations Pharmacology Play Population Proteins Receptor Activation Receptor Inhibition Receptor Signaling Recombinants Recurrence Refractory Resolution Role Seizures Spinal Ganglia Synapses Testing Therapeutic Therapeutic Effect Therapeutic Index Treatment Efficacy antagonist cell type experimental study high risk hippocampal pyramidal neuron inhibitor innovation mossy fiber neurotransmission pain behavior pain model patch clamp postsynaptic pre-clinical receptor receptor sensitivity side effect

项目摘要

SUMMARY Perampanel (PMP) is a third-generation anticonvulsant that acts as a noncompetitive allosteric modulator (NAM) of AMPA receptors, the ionotropic glutamate receptors (iGluRs) that serve as principle mediators of excitatory neurotransmission in the CNS. Its anticonvulsant activity is thought to result from dampening hyperexcitability in an epileptic brain through AMPA receptor inhibition. The recent structural resolution of the binding site for PMP on the GluA2 AMPA receptor subunit revealed fine details into determinants of its NAM activity but also underscored the conservation of critical binding residues in AMPA and kainate receptor (KAR) subunits, a distinct but related family of iGluRs. KARs serve a variety of functions in the CNS that are generally characterized as modulating a balance between excitation and inhibition tone. We hypothesize that PMP acts as a NAM on KARs and that this activity in part contributes to its therapeutic efficacy. Our preliminary results provide initial tentative support for this hypothesis and additionally reveal that PMP inhibition depends on the incorporation of a specific KAR subunit, GluK5, into the receptor complex. In this project, we propose to explore this observation further in three related aims. In Specific Aim 1, we will test the hypothesis that PMP is a subunit-selective noncompetitive antagonist of KARs and explore the importance of key amino acid residues in the PMP binding domains that control sensitivity of KARs to the modulator. In Specific Aim 2, we will test if PMP inhibits neuronal KARs at hippocampal mossy fiber synapses on CA3 pyramidal neurons and in dorsal root ganglion neurons. Both of these types of neuronal receptors are known to contain the GluK5 subunit. We will compare relative inhibition of receptors in wildtype and GluK5-/- mice to test the hypothesis that GluK5 forms a key substrate for PMP inhibition in the CNS. In Specific Aim 3, we will discriminate between modulatory activity on AMPA vs. kainate receptors by comparing potency of PMP in wildtype and GluK5-/- knockout mice in animal seizure, anxiety, and pain models, indications in which PMP shows efficacy. These objectives are significant because they could change our understanding of the mechanism of action of the third-generation anticonvulsant perampanel. Optimization of inhibitors that effectively discriminate between AMPA and kainate receptors could lead to a new generation of drugs with larger therapeutic indices.

总结