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

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.