Gq-coupled muscarinic receptor enhancement of KCNQ2/3 channels and activation of TRPC channels in multimodal control of excitability in dentate gyrus granule cells

Chase M. Carver, Mark S. Shapiro

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

KCNQ (Kv7, “M-type”) K + channels and TRPC (transient receptor potential, “canonical”) cation channels are coupled to neuronal discharge properties and are regulated via G q/11 -protein-mediated signals. Stimulation of G q/11 -coupled receptors both consumes phosphatidylinositol 4,5-bisphosphate (PIP 2 ) via phosphalipase Cβ hydrolysis and stimulates PIP 2 synthesis via rises in Ca 2+ i and other signals. Using brain-slice electrophysiology and Ca 2+ imaging from male and female mice, we characterized threshold K + currents in dentate gyrus granule cells (DGGCs) and CA1 pyramidal cells, the effects of G q/11 -coupled muscarinic M 1 acetylcholine (M 1 R) stimulation on M current and on neuronal discharge properties, and elucidated the intracellular signaling mechanisms involved. We observed disparate signaling cascades between DGGCs and CA1 neurons. DGGCs displayed M 1 R enhancement of M-current, rather than suppression, due to stimulation of PIP 2 synthesis, which was paralleled by increased PIP 2 -gated G-protein coupled inwardly rectifying K + currents as well. Deficiency of KCNQ2-containing M-channels ablated the M 1 R-induced enhancement of M-current in DGGCs. Simultaneously, M 1 R stimulation in DGGCs induced robust increases in [Ca 2+ ] i , mostly due to TRPC currents, consistent with, and contributing to, neuronal depolarization and hyperexcitability. CA1 neurons did not display such multimodal signaling, but rather M current was suppressed by M 1 R stimulation in these cells, similar to the previously described actions of M 1 R stimulation on M-current in peripheral ganglia that mostly involves PIP 2 depletion. Therefore, these results point to a pleiotropic network of cholinergic signals that direct cell-type-specific, precise control of hippocampal function with strong implications for hyperexcitability and epilepsy.

Original languageEnglish (US)
Pages (from-to)1566-1587
Number of pages22
JournalJournal of Neuroscience
Volume39
Issue number9
DOIs
StatePublished - Feb 27 2019

Keywords

  • Electrophysiology
  • Hippocampus
  • Hyperexcitability
  • Muscarinic receptors
  • Potassium channel
  • Signal transduction

ASJC Scopus subject areas

  • Neuroscience(all)

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