TY - JOUR T1 - Heteromeric TRPC1/TRPC4 Channels Play a Critical Role in Epileptiform Burst Firing and Seizure-induced Neurodegeneration JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.075341 SP - mol.111.075341 AU - Kevin D Phelan AU - Matthew M Mock AU - Oliver Kretz AU - U T Shwe AU - Maxim Kozhemyakin AU - L. John Greenfield AU - Alexander Dietrich AU - Lutz Birnbaumer AU - Marc Freichel AU - Veit Flockerzi AU - Fang Zheng Y1 - 2011/01/01 UR - http://molpharm.aspetjournals.org/content/early/2011/12/07/mol.111.075341.abstract N2 - Canonical transient receptor channels (TRPCs) are receptor-operated cation channels which are activated in response to phospholipase C signaling. Although TRPC1 is ubiquitously expressed in the brain, TRPC4 expression is the most restrictive, with the highest expression level limited to the lateral septum. The subunit composition of neuronal TRPC channels remains uncertain because of conflicting data from recombinant expression systems. Here we report that the large depolarizing plateau potential that underlies the epileptiform burst firing induced by metabotropic glutamate receptor agonists in lateral septal neurons was completely abolished in TRPC1/4 double knockout mice, and was abolished in 74% of lateral septal neurons in TRPC1 knockout mice. Furthermore, neuronal cell death in the lateral septum and the CA1 region of hippocampus after pilocarpine-induced severe seizures was significantly ameliorated in TRPC1/4 double knockout mice. Our data suggest that both TRPC1 and TRPC4 are essential for an intrinsic membrane conductance mediating the plateau potential in lateral septal neurons, possibly as heteromeric channels. Moreover, excitotoxic neuronal cell death, an underlying process for many neurological diseases, is not merely mediated by ionotropic glutamate receptors, but also by heteromeric TRPC channels activated by metabotropic glutamate receptors. TRPC channels could be an unsuspected but critical molecular target for clinical intervention for excitotoxicity. ER -