PMID- 38537434
OWN - NLM
STAT- MEDLINE
DCOM- 20240405
LR  - 20240410
IS  - 1532-1991 (Electronic)
IS  - 0143-4160 (Linking)
VI  - 119
DP  - 2024 May
TI  - STIM2 variants regulate Orai1/TRPC1/TRPC4-mediated store-operated Ca(2+) entry 
      and mitochondrial Ca(2+) homeostasis in cardiomyocytes.
PG  - 102871
LID - S0143-4160(24)00029-0 [pii]
LID - 10.1016/j.ceca.2024.102871 [doi]
AB  - The stromal interaction molecules (STIMs) are the sarcoplasmic reticulum (SR) 
      Ca(2+) sensors that trigger store-operated Ca(2+) entry (SOCE) in a variety of 
      cell types. While STIM1 isoform has been the focus of the research in cardiac 
      pathophysiology, the function of the homolog STIM2 remains unknown. Using Ca(2+) 
      imaging and patch-clamp techniques, we showed that knockdown (KD) of STIM2 by 
      siRNAs increased SOCE and the I(SOC) current in neonatal rat ventricular 
      cardiomyocytes (NRVMs). Within this cardiomyocyte model, we identified the 
      transcript expression of Stim2.1 and Stim2.2 splice variants, with predominance 
      for Stim2.2. Using conventional and super-resolution confocal microscopy (STED), 
      we found that exogenous STIM2.1 and STIM2.2 formed pre-clusters with a reticular 
      organization at rest. Following SR Ca(2+) store depletion, some STIM2.1 and 
      STIM2.2 clusters were translocated to SR-plasma membrane (PM) junctions and 
      co-localized with Orai1. The overexpression strategy revealed that STIM2.1 
      suppressed Orai1-mediated SOCE and the I(SOC) current while STIM2.2 enhanced 
      SOCE. STIM2.2-enhanced SOCE was also dependent on TRPC1 and TRPC4. Even if STIM2 
      KD or splice variants overexpression did not affect cytosolic Ca(2+) cycling, we 
      observed, using Rhod-2/AM Ca(2+) imaging, that Orai1 inhibition or STIM2.1 
      overexpression abolished the mitochondrial Ca(2+) (mCa(2+)) uptake, as opposed to 
      STIM2 KD. We also found that STIM2 was present in the mitochondria-associated 
      endoplasmic reticulum (ER) membranes (MAMs) by interacting with the inositol 
      trisphosphate receptors (IP(3)Rs), voltage-dependent anion channel (VDAC), 
      mitochondrial Ca(2+) uniporter (MCU), and mitofusin-2 (MNF2). Our results 
      suggested that, in NRVMs, STIM2.1 constitutes the predominant functional variant 
      that negatively regulates Orai1-generated SOCE. It participates in the control of 
      mCa(2+) uptake capacity possibly via the STIM2-IP(3)Rs-VDAC-MCU and MNF2 complex.
CI  - Copyright (c) 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.
FAU - Luo, Rui
AU  - Luo R
AD  - Inserm, UMR-S 1180, Signalisation et Physiopathologie Cardiovasculaire, 
      Universite Paris-Saclay, 91400 Orsay, France.
FAU - Gourrierec, Pauline Le
AU  - Gourrierec PL
AD  - Inserm, UMR-S 1180, Signalisation et Physiopathologie Cardiovasculaire, 
      Universite Paris-Saclay, 91400 Orsay, France.
FAU - Antigny, Fabrice
AU  - Antigny F
AD  - Inserm, UMR-S 999 << Hypertension pulmonaire: Physiopathologie et Innovation 
      Therapeutique >>, Hopital Marie Lannelongue, Le Plessis-Robinson, France; 
      Universite Paris-Saclay, Faculte de Medecine, Le Kremlin-Bicetre, France.
FAU - Bedouet, Kaveen
AU  - Bedouet K
AD  - Inserm, UMR-S 1180, Signalisation et Physiopathologie Cardiovasculaire, 
      Universite Paris-Saclay, 91400 Orsay, France.
FAU - Domenichini, Severine
AU  - Domenichini S
AD  - Universite Paris-Saclay, Inserm, CNRS, Ingenierie et Plateformes au Service de 
      l'Innovation Therapeutique-Plateforme MIPSIT, Orsay, France.
FAU - Gomez, Ana-Maria
AU  - Gomez AM
AD  - Inserm, UMR-S 1180, Signalisation et Physiopathologie Cardiovasculaire, 
      Universite Paris-Saclay, 91400 Orsay, France.
FAU - Benitah, Jean-Pierre
AU  - Benitah JP
AD  - Inserm, UMR-S 1180, Signalisation et Physiopathologie Cardiovasculaire, 
      Universite Paris-Saclay, 91400 Orsay, France.
FAU - Sabourin, Jessica
AU  - Sabourin J
AD  - Inserm, UMR-S 1180, Signalisation et Physiopathologie Cardiovasculaire, 
      Universite Paris-Saclay, 91400 Orsay, France. Electronic address: 
      jessica.sabourin@universite-paris-saclay.fr.
LA  - eng
PT  - Journal Article
DEP - 20240319
PL  - Netherlands
TA  - Cell Calcium
JT  - Cell calcium
JID - 8006226
RN  - SY7Q814VUP (Calcium)
RN  - 0 (Calcium Channels)
RN  - 0 (ORAI1 Protein)
RN  - 0 (Orai1 protein, rat)
RN  - 0 (Stromal Interaction Molecule 1)
RN  - 0 (Stim1 protein, rat)
SB  - IM
MH  - Animals
MH  - Rats
MH  - Biological Transport
MH  - *Calcium/metabolism
MH  - Calcium Channels/metabolism
MH  - Calcium Signaling
MH  - Homeostasis
MH  - Mitochondria/metabolism
MH  - *Myocytes, Cardiac/metabolism
MH  - ORAI1 Protein/metabolism
MH  - *Stromal Interaction Molecule 1/genetics/metabolism
OTO - NOTNLM
OT  - Cardiomyocytes
OT  - MAMs
OT  - Orai1
OT  - STIM2
OT  - STIM2.1
OT  - STIM2.2
OT  - Store-operated Ca(2+) entry
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2024/03/28 00:45
MHDA- 2024/04/05 06:44
CRDT- 2024/03/27 19:07
PHST- 2023/10/22 00:00 [received]
PHST- 2024/02/29 00:00 [revised]
PHST- 2024/03/07 00:00 [accepted]
PHST- 2024/04/05 06:44 [medline]
PHST- 2024/03/28 00:45 [pubmed]
PHST- 2024/03/27 19:07 [entrez]
AID - S0143-4160(24)00029-0 [pii]
AID - 10.1016/j.ceca.2024.102871 [doi]
PST - ppublish
SO  - Cell Calcium. 2024 May;119:102871. doi: 10.1016/j.ceca.2024.102871. Epub 2024 Mar 
      19.