STIM2 Membrane Protein Introduction

Introduction of STIM2

Stromal interaction molecule 2 (STIM2) is a transmembrane protein that is present in the endoplasmic reticulum (ER) and regulates store-operated Ca²⁺ entry (SOCE). STIM2 is the predominant protein in murine dendritic cells, mammary epithelial cells during lactation, human melanocytes, mouse spinal cord dorsal horn neurons, forebrain and hippocampus. The human STIM2 protein is encoded by STIM2 gene that is located on chromosome 4 region 15.2 (4p15.2). Alternative splicing produces three mRNA isoforms, the already known variant (Stim2.2, also STIM2α), a new shorter variant (Stim2.3), and a third larger splicing variant (Stim2.1; also STIM2β). Protein translation produces a single transmembrane proprotein that contains an endoplasmic reticulum (ER) signal peptide, a highly Ca²⁺ binding canonical EF-hand motif (cEF-hand) in the N-terminal region, followed by a hidden EF-hand motif (hEF-hand) and a sterile alpha motif (SAM), both located in the cavity area of the ER. The cEF-hand motif is a Ca²⁺sensor, while the hEF-hand and SAM domains are critical for maintaining the stability of the N-terminal region and oligomerization between the STIM proteins, respectively. The C-terminal region is located in the cytoplasmic compartment and separated from the N-terminal region by a single transmembrane domain. The C-terminal region contains the ezrin/radixin/moesin domain and is highly conserved in the STIM isoform, which includes two coiled-coil structures. This region mediates the interaction between the STIM1 and TRPC Ca²⁺ channels.

The Function of STIM2 Membrane Protein

In most cell types, the release of ER Ca²⁺ triggers storage operation of Ca²⁺ entry (SOCE), a form of Ca²⁺ influx in various cells which is regulated by the ER-resident STIM proteins. Stromal interaction molecule 1 (STIM1, a Ca²⁺ sensor) along with Orai1 (a Ca²⁺ entry channel) are the main proteins responsible for SOCE. STIM2 is a second ER-localized Ca²⁺ sensor protein that has been associated with SOCE and Ca²⁺ signaling. However, STIM2 is a poor activator of Orai1 and SOCE as compared to STIM1. STIM2 appears to play a complementary role in the control of intracellular Ca²⁺ homeostasis when STIM1 is prominently present. STIM2 can also act as an adaptor protein and increase the sensitivity of STIM1 to Ca²⁺ changes in ER by promoting recruitment of STIM1 to the endoplasmic reticulum (ER) and plasma membrane (PM) (ER-PM) junctions. In addition, STIM2 participates in the turnover of cholesterol content in neuronal PM and plays an important role in the nervous system. Moreover, STIM2 has also been proposed as a relevant player in pathological conditions related to aging, Alzheimer's and Huntington's diseases, autoimmune disorders and cancer.

Fig.1 The molecular structure of the STIM2 variant. The N-terminal region of the ER cavity includes a Ca²⁺ binding canonical EF-hand motif (cEF), hidden EF-hand (hEF) motif and a sterile alpha motif (SAM). The cytoplasmic C-terminal region includes CC regions (CC1 and CC2). (Rosado, 2015)

Application of STIM2 Membrane Protein Literature

1. Berna-Erro A., et al. Role of STIM2 in cell function and physiopathology. Journal of Physiology. 2017, 595(10):3111-3128. PubMed ID:28087881
   
   

   This review summarizes the role of STIM2 in the nervous system, the immune system, and anti-aging and cancer-related pathological conditions, and updates current knowledge of STIM2 function.

2. Yap K.A., et al. STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses. Neurobiology of learning and memory. 2017, 138:54-61. PubMed ID:27544849
   
   

   This article suggests that STIM2 promotes synaptic delivery and AMPA receptor removal, and regulates activity-dependent changes in synaptic strength through a unique communication pattern between endoplasmic reticulum and synapses.

3. Popugaeva E., et al. STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity. Molecular Neurodegeneration. 2015, 10:37. PubMed ID:26275606
   
   

   This article suggests that expression of STIM2 protein rescues calcium-calmodulin-dependent kinase II (CaMKII) activity and protects mushroom spines from amyloid toxicity in vitro and in vivo.

4. Rana A., et al. Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels. Journal of Cell Biology. 2015, 209(5):653-69. PubMed ID:26033257
   
   

   This article reveals that alternative splicing of the STIM protein family creates negative and positive regulators of SOCE to shape the amplitude and dynamics of Ca(2+) signals.

5. Garcia-Alvarez G., et al. STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs. Molecular Biology of the Cell. 2015, 26(6):1141-59. PubMed ID:25609091
   
   

   This article suggests that STIM2 regulates GluA1 phosphorylation by coupling PKA to AMPAR in a SOCE-independent manner and promotes cAMP-dependent GluA1 surface delivery through a combination of exocytosis and endocytosis.

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Reference

1. Rosado J A, et al. (2015). STIM and Orai1 Variants in Store-Operated Calcium Entry. Frontiers in Pharmacology. 6(ra74):325.

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