TY - JOUR
T1 - Gq-coupled muscarinic receptor enhancement of KCNQ2/3 channels and activation of TRPC channels in multimodal control of excitability in dentate gyrus granule cells
AU - Carver, Chase M.
AU - Shapiro, Mark S.
N1 - Funding Information:
This work was supported by the National Institutes of Health Grants R01 NS094461 and R01 NS043394 to M.S.S.; Presidential Scholar award to M.S.S., and a postdoctoral training fellowship to C.M.C. from Training Grant T32 HL007446 (James D. Stockand, PI). The authors wish to thank Isamar Sanchez and Maryann Hobbs for expert technical assistance with this project.
Publisher Copyright:
© 2019 the authors.
PY - 2019/2/27
Y1 - 2019/2/27
N2 - 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.
AB - 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.
KW - Electrophysiology
KW - Hippocampus
KW - Hyperexcitability
KW - Muscarinic receptors
KW - Potassium channel
KW - Signal transduction
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U2 - 10.1523/JNEUROSCI.1781-18.2018
DO - 10.1523/JNEUROSCI.1781-18.2018
M3 - Article
C2 - 30593498
AN - SCOPUS:85062273917
VL - 39
SP - 1566
EP - 1587
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 9
ER -