Abstract
Recently, we have reported that transient receptor potential channel-6 (TRPC6) plays an important role in the regulation of neuronal excitability and synchronization of spiking activity in the dentate granule cells (DGC). However, the underlying mechanisms of TRPC6 in these phenomena have been still unclear. In the present study, we investigated the role of TRPC6 in subcellular localization of Kv4.3 and its relevance to neuronal excitability in the rat hippocampus. TRPC6 knockdown increased excitability and inhibitory transmission in the DGC and the CA1 neurons in response to a paired-pulse stimulus. However, TRPC6 knockdown impaired γ-aminobutyric acid (GABA)ergic inhibition in the hippocampus during and after high-frequency stimulation (HFS). TRPC6 knockdown reduced the Kv4.3 clusters in membrane fractions and its dendritic localization on DGC and GABAergic interneurons. TRPC6 knockdown also decreased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and the efficacy of 4-aminopyridine (4-AP) in neuronal excitability. An ERK1/2 inhibitor generated multiple population spikes in response to a paired-pulse stimulus, concomitant with reduced membrane Kv4.3 translocation. A TRPC6 activator (hyperforin) reversed the effects of TRPC knockdown, except paired-pulse inhibition. These findings provide valuable clues indicating that TRPC6-mediated ERK1/2 activation may regulate subcellular Kv4.3 localization in DGC and interneurons, which is cause-effect relationship between neuronal excitability and seizure susceptibility.
Highlights
Transient receptor potential channel-6 (TRPC6) regulates Ca2+ influx and extracellular signalregulated kinase 1/2 (ERK1/2) activity in the brain and thereby participates in synaptic plasticity and neuronal survival (Li et al, 2005; Du et al, 2010; Lin et al, 2013; Ko and Kang, 2017)
We have reported that down-regulation of TRPC6 expression increases the susceptibility to ictogenic stimuli and neuronal excitability combined with a high level of synchrony of neurons
Regarding to the inhibitory role of TRPC6 in NMDA receptor activation (Li et al, 2012; Shen et al, 2013), these findings indicate that TRPC6 knockdown may increase GABAergic inhibition by enhancing the responsiveness of NMDA receptor on interneurons
Summary
Transient receptor potential channel-6 (TRPC6) regulates Ca2+ influx and extracellular signalregulated kinase 1/2 (ERK1/2) activity in the brain and thereby participates in synaptic plasticity and neuronal survival (Li et al, 2005; Du et al, 2010; Lin et al, 2013; Ko and Kang, 2017). Down-regulations of A-type K+ channels impair fast-spiking in interneurons, and subsequently increase excitability in principal neurons (Bernard et al, 2004; Birnbaum et al, 2004). Since the subcellular Kv4.3 localization is regulated by intracellular Ca2+ level and ERK1/2 activity (Kollo et al, 2006; Kim et al, 2007; Setién et al, 2013), it is likely that TRPC6 may regulate neuronal excitability via ERK1/2-mediated Kv4.3 translocation in DGC and interneurons. In the present study, we explored this hypothesis, which has not been reported
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