Plasma membrane insertion of TRPC5 channels contributes to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons

Abstract

In cultured hippocampal neurons, transient receptor potential 5 (TRPC5) channels are translocated and inserted into plasma membranes of hippocampal neurons to generate nonselective cation (NSC) currents. We investigated whether TRPC5 channel translocation also contributes to the generation of NSC currents underlying the afterdepolarizations and plateau potentials (PPs) in hippocampal pyramidal cells that are induced by muscarinic receptor activation. Using a biotinylation assay to quantify the change in surface membrane proteins in acute hippocampal slices, we found that muscarinic stimulation significantly enhanced the levels of TRPC5 protein on the membrane surface but not those of TRPC1 or TRPC4 channels. We then investigated the pharmacological sensitivity of the cation current observed during muscarinic stimulation to determine if a component could be due to TRPC5 channels. The TRPC channel antagonists 2-APB and SKF96365 strongly depressed the generation of PPs, the underlying tail currents (I(tail)) and the associated dendritic Ca(2+) influx induced by muscarinic receptor activation in pyramidal neurons. High intracellular concentrations of ATP, which specifically inhibit TRPC5 channels, depressed I(tail). In addition, pretreatment with the calmodulin (CaM) inhibitor W-7, which depresses recombinant TRPC5 currents, inhibited both the cation current (I(tail)) and the surface insertion of TRPC5 channels. Finally, the phosphatidylinositide 3-kinase (PI(3)K) inhibitor wortmannin, which blocks translocation of TRPC5 channels in cell culture, also inhibited both the I(tail) and the surface insertion of TRPC5 channels. Therefore, we conclude that insertion of TRPC5 channels contributes to the generation of the prolonged afterdepolarizations following muscarinic stimulation. This altered plasma membrane expression of TRPC5 channels in pyramidal neurons may play an important role in the generation of prolonged neuronal depolarization and bursting during the epileptiform seizure discharges of epilepsy.

Canonical Transient Receptor Channel 5 (TRPC5) and TRPC1/4 Contribute to Seizure and Excitotoxicity by Distinct Cellular Mechanisms

“…Another possibility is that TRPC5 may normally remain in intracellular compartments and is only inserted into the membrane when m1AChRs or mGluR1 or mGluR5 receptors are activated. It has been reported that TRPC5 exhibits carbacholinduced membrane insertion whereas surface expression of TRPC1 and TRPC4 was unchanged after carbachol exposure (Tai et al, 2011). However, it should be noted that a dynamic regulation of surface expression of TRPC1 or TRPC4 has also been reported previously (Odell et al, 2005;Wang et al, 2007: Cheng et al, 2010.…”

“…At the cellular level, activation of m1 AChR results in a plateau potential similar to the one induced by activation of mGluRs. Although several studies have suggested that this plateau potential may be mediated by neuronal TRPC channels (Yan et al, 2009;Zhang et al, 2011;Tai et al, 2011), knocking out both TRPC1 and TRPC4, two highly expressed TRPCs, did not diminish the severity of pilocarpine-induced seizures (Phelan et al, 2012). This result suggests that heteromeric TRPC1/4 channels are not required for pilocarpineinduced seizures; however, TRPC5-containing channels could still be required.…”

“…Scale bars: 0.25 mm (A, B); 0.05 mm (C, D, F, G); 0.04 mm (E, H). could be mediated by TRPC5-containing channels (i.e., TRPC1/5, TRPC4/5, or TRPC1/4/5 channels) in cortical pyramidal neurons (Yan et al, 2009;Tai et al, 2011;Zhang et al, 2011). To test whether this is the case in the hippocampus, we recorded the spontaneous burst firing induced by 1S,3R-ACPD, an mGluR agonist, in pyramidal neurons of the CA1 region in adult mice (2 to 3 months old).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…In these cells, activation of TRPC5 seems to mediate the negative control of neurotrophin-3 on dendritic growth . In adults, TRPC5 in hippocampal pyramidal neurons is suggested to play a role in cholinergic plateau potential formation (Tai et al, 2011). Furthermore, TRPC5 is present both in the frontal (Fowler et al, 2007) and temporal (von Bohlen Und Halbach et al, 2005) cortex, where it might be involved in seizure generation (Phelan et al, 2013).…”

Molecular Determinants of the Sensitivity to Gq/11-Phospholipase C-dependent Gating, Gd3+ Potentiation, and Ca2+ Permeability in the Transient Receptor Potential Canonical Type 5 (TRPC5) Channel

“…Genetic ablation of TRPC5 also reduces pilocarpine-induced seizures, long term potentiation, and seizure-induced neuronal cell death in the mouse hippocampus (8,9). Plasma membrane insertion of TRPC5 in pyramidal hippocampal neurons is associated with the generation of prolonged cholinergic depolarization and bursting during epileptiform seizure discharges, suggesting that elevated TRPC5 activity may lead to an imbalance in hippocampal neuronal networks (10).…”