The role of canonical transient receptor potential channels in seizure and excitotoxicity.

Fang Zheng,Kevin Phelan

doi:10.3390/cells3020288

Abstract

Canonical transient receptor potential (TRPC) channels are a family of polymodal cation channels with some degree of Ca2+ permeability. Although initially thought to be channels mediating store-operated Ca2+ influx, TRPC channels can be activated by stimulation of Gq-coupled G-protein coupled receptors, or by an increase in intracellular free Ca2+ concentration. Thus, activation of TRPC channels could be a common downstream event of many signaling pathways that contribute to seizure and excitotoxicity, such as N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ influx, or metabotropic glutamate receptor activation. Recent studies with genetic ablation of various TRPC family members have demonstrated that TRPC channels, in particular heteromeric TRPC1/4 channels and homomeric TRPC5 channels, play a critical role in both pilocarpine-induced acute seizures and neuronal cell death. However, exact underlying mechanisms remain to be fully elucidated, and selective TRPC modulators and antibodies with better specificity are urgently needed for future research.

Highlights

Seizures arise from the synchronized burst firing of a large group of cortical neurons
It should be noted that the metabotropic glutamate receptors (mGluRs) agonist-induced plateau potential is present in a small group of lateral septal neurons in TRPC1KO mice, suggesting that homomeric TRPC4 channels are capable of mediating the plateau potential [33]
We studied the role of TRPC channels in seizure susceptibility and seizure-induced neuronal cell death, using the pilocarpine-induced status epilepticus model (Figure 3)

Summary

Introduction

Seizures arise from the synchronized burst firing of a large group of cortical neurons. Seizures can be induced by repetitive electric stimulations (i.e., kindling) of the perforant pathway in the hippocampus, or by chemical convulsants (e.g., the muscarinic agonist pilocarpine) that act on the hippocampal circuitry resulting in synchronized cortical firing. The hippocampus contains some of the neuronal populations that are most vulnerable to excitotoxicity, which is neuronal cell death caused by over-activation of glutamate receptors [1,2]. Loss of ATP-dependent membrane transport results in the collapse of ion gradients across cell membranes thereby initiating a vicious cycle: accumulation of extracellular K+ leads to membrane depolarization, which in turn exacerbates energy deficits and further destabilizes ion gradients. The collapse of ion gradients impairs clearance of glutamate from the synaptic cleft which floods the extracellular space with glutamate leading to widespread neuronal cell death. There are likely alternative signaling pathways leading to Ca2+ overload such as those involving metabotropic glutamate receptors (mGluRs), a family of G-protein coupled glutamate receptors [7]

The Role of Group I mGluRs in Seizure and Excitotoxicity

TRPC Channels and Epileptiform Burst Firing in the Hippocampus

Findings

Conclusions