Research progress on the role and mechanism of STIM and Orai protein-mediated store-operated calcium entry in cardiovascular diseases.
SOCE plays a complex role in cardiovascular diseases, and while inhibitors show promise in preclinical studies, clinical translation faces significant hurdles.
Where it sits
this study against the rest of the lypressin corpusSummary and findings
This review discusses the role of STIM and Orai proteins in store-operated calcium entry (SOCE) and their involvement in cardiovascular diseases. It highlights the complexity of SOCE regulation and the challenges in translating preclinical findings into clinical applications. The review also addresses the therapeutic potential and limitations of SOCE inhibitors.
Abstract
Store-operated calcium entry (SOCE) mediated by STIM and Orai proteins is a fundamental Ca<sup>2+</sup> influx mechanism that critically regulates intracellular calcium homeostasis and participates in cardiovascular pathophysiology. Upon endoplasmic reticulum Ca<sup>2+</sup> store depletion, STIM1/2 activate plasma membrane Orai1/3 channels, initiating Ca<sup>2+</sup> entry that drives vasoconstriction, smooth muscle proliferation, platelet activation, and cardiac hypertrophy. Dysregulated SOCE is closely associated with hypertension, atherosclerosis, pulmonary hypertension, and thromboembolic disorders. However, SOCE is not a simple binary pathway but operates within a complex regulatory network. Beyond the core STIM-Orai axis, auxiliary proteins including transient receptor potential canonical 1 (TRPC1), tetraspanin 18 (Tspan18), tropomyosin 3 (TPM3), SOCE-associated regulatory factor (SARAF), and A-kinase anchoring protein 79/150 (AKAP79/150) modulate SOCE amplitude, kinetics, and downstream signaling in a cell- and context-dependent manner. Moreover, the functional consequences of SOCE are highly heterogeneous: Orai1 protects adult cardiomyocytes but promotes pathological hypertrophy in neonatal cells, posing a therapeutic dilemma. Although preclinical studies have shown efficacy of SOCE inhibitors, clinical translation remains hindered by poor isoform selectivity, suboptimal pharmacokinetics, lack of tissue-specific delivery, disease-stage-dependent effects, and absence of validated biomarkers. Importantly, recent evidence has definitively ruled out amlodipine-induced CRAC channel activation at therapeutic concentrations, confirming it as an experimental artifact. This review systematically summarizes the molecular complexity, functional diversity, and translational barriers of STIM/Orai-mediated SOCE, aiming to inform precision therapeutic strategies for cardiovascular diseases.
Background
The study addresses the role of store-operated calcium entry (SOCE) in cardiovascular diseases, focusing on the STIM and Orai proteins. SOCE is crucial for intracellular calcium homeostasis and is implicated in various cardiovascular pathologies such as hypertension and atherosclerosis. Understanding the molecular mechanisms of SOCE is important for developing targeted therapies.
Methods
This is a review article that systematically summarizes existing research on the molecular complexity and functional diversity of STIM/Orai-mediated SOCE. It includes a discussion of auxiliary proteins and the regulatory network influencing SOCE, as well as translational barriers to clinical application.
Results
The review highlights that SOCE is not a binary pathway but part of a complex regulatory network involving multiple proteins. It notes the differential roles of Orai1 in adult and neonatal cardiomyocytes and the challenges in translating preclinical findings into clinical practice due to issues like poor isoform selectivity and lack of tissue-specific delivery.
Interpretation
The review provides a comprehensive overview of the challenges in targeting SOCE for cardiovascular diseases. While preclinical studies show potential, the clinical applicability is limited by pharmacokinetic issues and the complexity of SOCE regulation. The findings suggest that precision therapeutic strategies are needed to address these challenges.
Key findings
- SOCE is a fundamental Ca<sup>2+</sup> influx mechanism in cardiovascular pathophysiology.
- Dysregulated SOCE is associated with hypertension, atherosclerosis, and thromboembolic disorders.
- Orai1 protects adult cardiomyocytes but promotes hypertrophy in neonatal cells.
- Preclinical studies show efficacy of SOCE inhibitors, but clinical translation is challenging.
- Amlodipine-induced CRAC channel activation at therapeutic concentrations is an experimental artifact.
Limitations
- Review based on preclinical studies
- Challenges in clinical translation
- Poor isoform selectivity
- Suboptimal pharmacokinetics
- Lack of tissue-specific delivery