title: Heteromeric canonical transient receptor potential 1 and 4 channels play a critical role in epileptiform burst firing and seizure-induced neurodegeneration.
abstract: Canonical transient receptor potential channels (TRPCs) are receptor-operated cation channels that 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 cornu ammonis 1 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 mediated merely 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Phelan
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Mock
authors.forename: Oliver
authors.initials: O
authors.lastname: Kretz
authors.forename: U Thaung
authors.initials: UT
authors.lastname: Shwe
authors.forename: Maxim
authors.initials: M
authors.lastname: Kozhemyakin
authors.forename: L John
authors.initials: LJ
authors.lastname: Greenfield
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
mesh_terms: D000818:Animals; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D060888:Real-Time Polymerase Chain Reaction; D012640:Seizures / Q000503:physiopathology*; D050052:TRPC Cation Channels / Q000502:physiology*
chemical_list: D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C096351:transient receptor potential cation channel, subfamily C, member 1