Journal Article

Neuronal Nitric Oxide Synthase Regulates Cerebellar Parallel Fiber Slow EPSC in Purkinje Neurons by Modulating STIM1-Gated TRPC3-Containing Channels

Feng, Qingping, Inoue, Wataru, Xiang, Yun-Yan, Lu, Wei-Yang, Gui, Le, Tellios, Vasiliki

2024

Overview

Responding to burst stimulation of parallel fibers (PFs), cerebellar Purkinje neurons (PNs) generate a convolved synaptic response displaying a fast excitatory postsynaptic current (EPSC Fast ) followed by a slow EPSC (EPSC Slow ). The latter is companied with a rise of intracellular Ca 2+ and critical for motor coordination. The genesis of EPSC Slow in PNs results from activation of metabotropic type 1 glutamate receptor (mGluR1), oligomerization of stromal interaction molecule 1 (STIM1) on the membrane of endoplasmic reticulum (ER) and opening of transient receptor potential canonical 3 (TRPC3) channels on the plasma membrane. Neuronal nitric oxide synthase (nNOS) is abundantly expressed in PFs and granule neurons (GNs), catalyzing the production of nitric oxide (NO) hence regulating PF-PN synaptic function. We recently found that nNOS/NO regulates the morphological development of PNs through mGluR1-regulated Ca 2+ -dependent mechanism. This study investigated the role of nNOS/NO in regulating EPSC Slow . Electrophysiological analyses showed that EPSC Slow in cerebellar slices of nNOS knockout (nNOS −/− ) mice was significantly larger than that in wildtype (WT) mice. Activation of mGluR1 in cultured PNs from nNOS −/− mice evoked larger TRPC3-channel mediated currents and intracellular Ca 2+ rise than that in PNs from WT mice. In addition, nNOS inhibitor and NO-donor increased and decreased, respectively, the TRPC3-current and Ca 2+ rise in PNs. Moreover, the NO-donor effectively decreased TRPC3 currents in HEK293 cells expressing WT STIM1, but not cells expressing a STIM1 with cysteine mutants. These novel findings indicate that nNOS/NO inhibits TRPC3-containig channel mediated cation influx during EPSC Slow , at least in part, by S-nitrosylation of STIM1.

• Publisher: Springer US,Springer Nature B.V
• Subject: Biomedical and Life Sciences / Biomedicine / Calcium (intracellular) / Cerebellum / Endoplasmic reticulum / Excitatory postsynaptic potentials / Glutamate receptors / Glutamic acid receptors (metabotropic) / Granule cells / Intracellular / Neurobiology / Neurogenesis / Neurology / Neurosciences / Nitric oxide / Nitric-oxide synthase / Oligomerization / Parallel fibers / Purkinje cells / STIM1 protein / Synaptogenesis / Transient receptor potential proteins