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Monitoring Dynamic Changes In Mitochondrial Calcium Levels During Apoptosis Using A Genetically Encoded Calcium Sensor
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Exendin-4 alleviates Aβ1-40-induced apoptosis and calcium dysregulation in RPE cells through the CHP1/NHE1 complex

Qinxin Shu1, Yuxin Lin1, Wenqi Su1

  • 1Department of Ophthalmology, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong District, Chongqing 400016, China.

Biochemical Pharmacology
|February 12, 2026
PubMed

Insights

Exendin-4 (EX-4) protects against age-related macular degeneration (AMD) by targeting Calcineurin-like EF-hand protein 1 (CHP1). This interaction reduces apoptosis and restores calcium homeostasis, offering therapeutic potential for AMD treatment.

Area of Science:

  • Ophthalmology
  • Molecular Biology
  • Pharmacology

Background:

  • Age-related macular degeneration (AMD) is a major cause of vision loss in older adults, with limited effective treatments for dry AMD.
  • Exendin-4 (EX-4) exhibits anti-inflammatory, antioxidant, and antiapoptotic properties, and influences calcium homeostasis, but its role in AMD is unknown.
  • Developing novel therapeutic strategies for AMD is crucial due to the lack of effective interventions.

Purpose of the Study:

  • To investigate the protective effects of Exendin-4 (EX-4) against Aβ1-40-induced age-related macular degeneration (AMD).
  • To elucidate the underlying molecular mechanism and identify the direct target of EX-4 in AMD.
  • To assess the therapeutic potential of the EX-4/CHP1 interaction for AMD treatment.

Main Methods:

  • In vivo and in vitro experiments were conducted to evaluate the effects of EX-4 on apoptosis and calcium homeostasis.
  • Proteome microarrays and pulldown LC-MS/MS were used to identify the target protein of EX-4.
  • In vitro studies involved knocking down or overexpressing Calcineurin-like EF-hand protein 1 (CHP1).
  • Experiments were performed in AMD mice with CHP1-deficient retinas.

Main Results:

  • Pretreatment with EX-4 alleviated apoptosis and restored calcium homeostasis in AMD models.
  • EX-4 was found to bind directly to Calcineurin-like EF-hand protein 1 (CHP1), reducing its expression concentration-dependently.
  • The EX-4/CHP1 interaction reduced apoptosis and normalized intracellular Ca2+ levels via the CHP1/NHE1 complex.
  • CHP1 modulation reversed EX-4's effects on apoptosis and calcium signaling in vitro.
  • The therapeutic benefits of EX-4 in AMD mice were partially reduced in CHP1-deficient retinas.

Conclusions:

  • Exendin-4 (EX-4) demonstrates therapeutic potential for age-related macular degeneration (AMD).
  • The interaction between EX-4 and Calcineurin-like EF-hand protein 1 (CHP1) is a key mechanism underlying EX-4's protective effects.
  • Targeting the EX-4/CHP1 pathway may offer a novel strategy for treating AMD by alleviating apoptosis and restoring calcium homeostasis.
Keywords:
AMDApoptosisCHP1/NHE1Exendin-4RPE

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