Store-Operated Calcium Channels Are Involved in Spontaneous Slow Calcium Oscillations in Striatal Neurons

Abstract

The striatum plays an important role in linking cortical activity to basal ganglia output. Striatal neurons exhibit spontaneous slow Ca 2+ oscillations that result from Ca 2+ release from the endoplasmic reticulum (ER) induced by the mGluR5-IP3R signaling cascade. The maximum duration of a single oscillatory event is about 300 s. A major question arises as to how such a long-duration Ca 2+ elevation is maintained. Store-operated calcium channels (SOCCs) are one of the calcium (Ca 2+)-permeable ion channels. SOCCs are opened by activating the metabotropic glutamate receptor type 5 and inositol 1,4,5-trisphosphate receptor (mGluR5-IP3R) signal transduction cascade and are related to the pathophysiology of several neurological disorders. However, the functions of SOCCs in striatal neurons remain unclear. Here, we show that SOCCs exert a functional role in striatal GABAergic neurons. Depletion of calcium stores from the ER induced large, sustained calcium entry that was blocked by SKF96365, an inhibitor of SOCCs. Moreover, the application of SKF96365 greatly reduced the frequency of slow Ca 2+ oscillations. The present results indicate that SOCCs contribute to Ca 2+ signaling in striatal GABAergic neurons, including medium spiny projection neurons (MSNs) and GABAergic interneurons, through elevated Ca 2+ due to spontaneous slow Ca 2+ oscillations.

Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System

“…The molecular composition of SOCs in MSNs has not been well established. Kikuta et al (2019) found strong expression of Orai2, moderate expression of Orai3, and sparse expression of Orai1 in striatal GABAergic neurons with strong expression of both STIM1 and STIM2. Interestingly, knockdown of STIM1, Orai1, or TRPC1 proteins leads to dramatic reduction of SOCE in MSNs (Vigont et al, 2015), indicating STIM1, Orai1, and TRPC1 mediate SOCE in MSNs.…”

“…Additionally, a recent study demonstrates that deletion of TRPC1 largely reduced SOCE in MSNs (Wu J. et al, 2018), further indicating an important role of TRPC1 in MSN SOCE. In addition, SKF96365, a SOC and TRPC channel inhibitor, was found to reduce the frequency of spontaneous slow Ca 2+ oscillations in these neurons, indicating the SOCE has a role in Ca 2+ signaling in MSNs (Kikuta et al, 2019).…”

“…As the field of SOCs in neurological diseases is relatively nascent, data are limited and understanding of the role of Alvarez et al, 2015;Hou et al, 2015;González-Sánchez et al, 2017;Guner et al, 2017;Bouron, 2020 Hippocampal neurons Counteract continuous loss of Ca 2+ across the plasma membrane to maintain basal Ca 2+ homeostasis Synapse formation, maturation, and plasticity Samtleben et al, 2015;Segal and Korkotian, 2016;Korkotian et al, 2017;Yap et al, 2017 Striatal medium spiny neurons Involvement in spontaneous slow Ca 2+ oscillations Kikuta et al, 2019 Dopaminergic neurons Regulation of mitochondrial oxidative phosphorylation Activation of AKT/mTOR pathway Selvaraj et al, 2012;Sun et al, 2017;Surmeier et al, 2017 Purkinje neurons Clearance of cytosolic Ca 2+ during neuronal firing Modulation of neuronal excitability and intrinsic plasticity Refilling of calcium stores required for TRPC3 function Regulation of mGluR1/TRPC3-dependent slow excitatory synaptic potentials Cerebellar motor function Hartmann et al, 2014;Ryu et al, 2017;Shim et al, 2018;Jang et al, 2020 Cerebellar granule cells Involvement in spontaneous Ca 2+ oscillations Singaravelu et al, 2008 Spinal cord dorsal horn Regulation of resting calcium homeostasis, A type potassium channels, and neuronal excitability Xia et al, 2014 Dorsal root ganglion neurons Modulation of neuronal excitability Wei et al, 2017 Astrocytes Gliotransmitter release/gliotransmission Tonic inhibition of CA1 pyramidal neurons Cytokine secretion Handy et al, 2017;Toth et al, 2019 Muller glia Depletion dependent Ca 2+ homeostasis Molnar et al, 2016 Microglia Cellular migration Phagocytosis Cytokine secretion NFAT1 activity Ikeda et al, 2013;Heo et al, 2015;Michaelis et al, 2015;Lim et al, 2017 FIGURE 1 | Schematic showing the different regions and cells of the nervous system where store-operated calcium entry (SOCE) has been shown to regulated cellular processes and the related pathologies linked to dysfunction of SOCE in these regions.…”

Manganese Dynamics in Mouse Brain After Systemic MnCl2 Administration for Activation-Induced Manganese-Enhanced MRI

“…As mentioned in the introduction, Mn 2+ is known to be a surrogate marker for Ca 2+ , hence AIM-MRI can measure changes in neural activity by evaluating the R1 map. However, we need to be aware that Mn 2+ can pass through not only VDCCs but also other Ca 2+ -permeable channels, such as some ligand-gated channels and store-operated calcium channels ( Uehara et al, 2002 ; Itoh et al, 2008 ; Tu et al, 2009 ; Chen et al, 2015 ; Bouabid et al, 2016 ; Kikuta et al, 2019 ). The inositol 1,4,5-trisphosphate receptor on the endoplasmic reticulum membrane is also permeable to Mn 2+ ( Striggow and Ehrlich, 1996 ).…”