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Upregulated TRPM1 is associated with apoptosis in Rs1 knockout mice and in ARPE19 cells through increased
Weiping Wang1,2, Jingyang Liu1,2, Xiuxiu Jin1,2
1Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China.
Abstract:
The pathological mechanism underlying retinal apoptosis in X-linked retinoschisis (XLRS), a disease caused by retinoschisin 1 (RS1) deficiency, remains incompletely understood. This study aimed to investigate the role of transient receptor potential melastatin 1 (TRPM1) in retinal tissues and cells. Retinal function and structure were assessed by electroretinography (ERG) and optical coherence tomography (OCT). Protein expression was evaluated by immunofluorescence staining and western blotting (WB). Retinal morphology was examined by hematoxylin and eosin (H&E) staining. Apoptotic retinal cells were detected by TUNEL staining. Key proteins were screened using proteomics data obtained by mass spectrometry. Intracellular calcium levels were measured using Rhod-2 AM. TRPM1 expression in Rs1-KO mice was 1.3-fold higher than that in wild-type mice (p < 0.05), whereas TRPM1-overexpressing ARPE19 cells exhibited approximately twofold higher expression than the empty vector control group. Mechanistically, TRPM1-mediated calcium influx promoted calcium/calmodulin-dependent protein kinase II (CAMKII) phosphorylation. Concomitantly, the accumulation of the autophagy-related proteins P62 and LC3B, increased BAX expression, and decreased BCL2 expression were observed in both Rs1-KO retinal tissues and TRPM1-overexpressing ARPE19 cells. These findings collectively suggest that TRPM1 may contribute to cell's apoptosis. Our study provides new insight into the mechanism of retinal apoptosis in XLRS.
Insights
Transient receptor potential melastatin 1 (TRPM1) may drive retinal apoptosis in X-linked retinoschisis (XLRS) by increasing calcium influx. This study reveals TRPM1 as a potential contributor to retinal cell death in XLRS.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- X-linked retinoschisis (XLRS) is a genetic disorder causing retinal degeneration due to retinoschisin 1 (RS1) deficiency.
- The precise pathological mechanisms leading to retinal apoptosis in XLRS are not fully elucidated.
Purpose of the Study:
- To investigate the role of transient receptor potential melastatin 1 (TRPM1) in the retinal apoptosis observed in XLRS.
- To explore the molecular pathways involving TRPM1 in retinal cells and tissues.
Main Methods:
- Utilized Rs1-knockout (KO) mice and TRPM1-overexpressing ARPE19 cells.
- Assessed retinal structure and function using electroretinography (ERG) and optical coherence tomography (OCT).
- Analyzed protein expression via immunofluorescence, Western blotting, proteomics, and measured intracellular calcium levels.
Main Results:
- TRPM1 expression was significantly elevated in Rs1-KO mice and TRPM1-overexpressing cells.
- TRPM1-mediated calcium influx led to increased phosphorylation of CAMKII.
- Observed altered expression of autophagy markers (P62, LC3B) and apoptosis regulators (BAX, BCL2) consistent with cell death.
Conclusions:
- TRPM1 activation contributes to retinal cell apoptosis in the context of RS1 deficiency.
- TRPM1-mediated calcium signaling is a key pathway implicated in XLRS pathogenesis.
- Findings offer new insights into therapeutic targets for XLRS.
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