PMID- 35418597
OWN - NLM
STAT- MEDLINE
DCOM- 20220415
LR  - 20220527
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 12
IP  - 1
DP  - 2022 Apr 13
TI  - Oscillatory calcium release and sustained store-operated oscillatory calcium 
      signaling prevents differentiation of human oligodendrocyte progenitor cells.
PG  - 6160
LID - 10.1038/s41598-022-10095-1 [doi]
LID - 6160
AB  - Endogenous remyelination in demyelinating diseases such as multiple sclerosis is 
      contingent upon the successful differentiation of oligodendrocyte progenitor 
      cells (OPCs). Signaling via the Galpha(q)-coupled muscarinic receptor (M(1/3)R) 
      inhibits human OPC differentiation and impairs endogenous remyelination in 
      experimental models. We hypothesized that calcium release following Galpha(q)-coupled 
      receptor (G(q)R) activation directly regulates human OPC (hOPC) cell fate. In 
      this study, we show that specific G(q)R agonists activating muscarinic and 
      metabotropic glutamate receptors induce characteristic oscillatory calcium 
      release in hOPCs and that these agonists similarly block hOPC maturation in 
      vitro. Both agonists induce calcium release from endoplasmic reticulum (ER) 
      stores and store operated calcium entry (SOCE) likely via STIM/ORAI-based 
      channels. siRNA mediated knockdown (KD) of obligate calcium sensors STIM1 and 
      STIM2 decreased the magnitude of muscarinic agonist induced oscillatory calcium 
      release and attenuated SOCE in hOPCs. In addition, STIM2 expression was necessary 
      to maintain the frequency of calcium oscillations and STIM2 KD reduced 
      spontaneous OPC differentiation. Furthermore, STIM2 siRNA prevented the effects 
      of muscarinic agonist treatment on OPC differentiation suggesting that SOCE is 
      necessary for the anti-differentiative action of muscarinic receptor-dependent 
      signaling. Finally, using a gain-of-function approach with an optogenetic STIM 
      lentivirus, we demonstrate that independent activation of SOCE was sufficient to 
      significantly block hOPC differentiation and this occurred in a frequency 
      dependent manner while increasing hOPC proliferation. These findings suggest that 
      intracellular calcium oscillations directly regulate hOPC fate and that 
      modulation of calcium oscillation frequency may overcome inhibitory Galpha(q)-coupled 
      signaling that impairs myelin repair.
CI  - (c) 2022. The Author(s).
FAU - Seidman, Richard A
AU  - Seidman RA
AD  - Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, 
      University at Buffalo, Buffalo, NY, USA.
FAU - Khattab, Heba
AU  - Khattab H
AD  - Department of Pharmacology and Toxicology, Jacob's School of Medicine and 
      Biomedical Sciences, University at Buffalo, 955 Main Street, Buffalo, NY, 14203, 
      USA.
FAU - Polanco, Jessie J
AU  - Polanco JJ
AD  - Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, 
      University at Buffalo, Buffalo, NY, USA.
FAU - Broome, Jacqueline E
AU  - Broome JE
AD  - Department of Pharmacology and Toxicology, Jacob's School of Medicine and 
      Biomedical Sciences, University at Buffalo, 955 Main Street, Buffalo, NY, 14203, 
      USA.
FAU - Sim, Fraser J
AU  - Sim FJ
AD  - Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, 
      University at Buffalo, Buffalo, NY, USA. fjsim@buffalo.edu.
AD  - Department of Pharmacology and Toxicology, Jacob's School of Medicine and 
      Biomedical Sciences, University at Buffalo, 955 Main Street, Buffalo, NY, 14203, 
      USA. fjsim@buffalo.edu.
LA  - eng
GR  - UL1 TR001412/TR/NCATS NIH HHS/United States
GR  - UL1TR001412-S1/TR/NCATS NIH HHS/United States
GR  - R01NS104021/NS/NINDS NIH HHS/United States
GR  - R01 NS104021/NS/NINDS NIH HHS/United States
GR  - R25GM09545902/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220413
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Calcium, Dietary)
RN  - 0 (Muscarinic Agonists)
RN  - 0 (ORAI1 Protein)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Stromal Interaction Molecule 1)
RN  - 0 (Stromal Interaction Molecule 2)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium/metabolism
MH  - *Calcium Signaling/physiology
MH  - Calcium, Dietary/metabolism
MH  - Humans
MH  - Muscarinic Agonists/pharmacology
MH  - ORAI1 Protein/metabolism
MH  - *Oligodendrocyte Precursor Cells/metabolism
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Stromal Interaction Molecule 1/genetics/metabolism
MH  - Stromal Interaction Molecule 2/metabolism
PMC - PMC9007940
COIS- The authors declare no competing interests.
EDAT- 2022/04/15 06:00
MHDA- 2022/04/16 06:00
PMCR- 2022/04/13
CRDT- 2022/04/14 05:18
PHST- 2021/05/14 00:00 [received]
PHST- 2022/03/31 00:00 [accepted]
PHST- 2022/04/14 05:18 [entrez]
PHST- 2022/04/15 06:00 [pubmed]
PHST- 2022/04/16 06:00 [medline]
PHST- 2022/04/13 00:00 [pmc-release]
AID - 10.1038/s41598-022-10095-1 [pii]
AID - 10095 [pii]
AID - 10.1038/s41598-022-10095-1 [doi]
PST - epublish
SO  - Sci Rep. 2022 Apr 13;12(1):6160. doi: 10.1038/s41598-022-10095-1.