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 Gq/11-protein-mediated signals. Stimulation of Gq/11-coupled receptors both consumes phosphatidylinositol 4,5-bisphosphate (PIP2) via phosphalipase Cβ hydrolysis and stimulates PIP2 synthesis via rises in Ca2+ i and other signals. Using brain-slice electrophysiology and Ca2+ imaging from male and female mice, we characterized threshold K+ currents in dentate gyrus granule cells (DGGCs) and CA1 pyramidal cells, the effects of Gq/11-coupled muscarinic M1 acetylcholine (M1R) 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 M1R enhancement of M-current, rather than suppression, due to stimulation of PIP2 synthesis, which was paralleled by increased PIP2-gated G-protein coupled inwardly rectifying K+ currents as well. Deficiency of KCNQ2-containing M-channels ablated the M1R-induced enhancement of M-current in DGGCs. Simultaneously, M1R stimulation in DGGCs induced robust increases in [Ca2+]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 M1R stimulation in these cells, similar to the previously described actions of M1R stimulation on M-current in peripheral ganglia that mostly involves PIP2 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.SIGNIFICANCE STATEMENT At the neuronal membrane, protein signaling cascades consisting of ion channels and metabotropic receptors govern the electrical properties and neurotransmission of neuronal networks. Muscarinic acetylcholine receptors are G-protein-coupled metabotropic receptors that control the excitability of neurons through regulating ion channels, intracellular Ca2+ signals, and other second-messenger cascades. We have illuminated previously unknown actions of muscarinic stimulation on the excitability of hippocampal principal neurons that include M channels, TRPC (transient receptor potential, "canonical") cation channels, and powerful regulation of lipid metabolism. Our results show that these signaling pathways, and mechanisms of excitability, are starkly distinct between peripheral ganglia and brain, and even between different principal neurons in the hippocampus.