Work

Proton activated chloride channel and its regulation of insulin secretion in β cells

Year: 2025

Type: article

Abstract: Type II diabetes is a prevalent chronic disease worldwide, yet no curative treatment currently exists. Compromised insulin release is one of the hallmarks of type II diabetes, to restore insulin release is one standard to screen candidates for therapy. Proton-activated chloride (PAC) channels are pH-sensitive chloride channels that open under acidic conditions, but their potential role in pancreatic β-cell physiology and diabetes has not been fully explored. In this study, we identified PAC on the membrane of pancreatic β-cells and found it to be closely associated with insulin secretory granules. Immunostaining and FRET imaging revealed that PAC is co-localized with Syntaxin 1 A and CaV1.2. Overexpression and knockdown of PAC increased and reduced L type calcium currents and steady capacitance jumps which reflect fast insulin secretion. Furthermore, manipulation of PAC expression significantly altered overall insulin release under high glucose conditions in vitro. Knockout of PAC channels in mice, however, affects body weight, fasting blood glucose levels, and serum insulin levels when constructing a type II diabetes model through high-fat diet feeding, compared to wild-type mice or Pac knockout mice fed a normal diet. Together, these findings reveal a previously unrecognized role for PAC in regulating both phases of insulin secretion and suggest that PAC channels could represent a novel therapeutic target for improving β-cell function and treating diabetes. Given the global burden of type II diabetes, understanding PAC channel function could open new avenues for targeted interventions to restore insulin secretion and improve disease outcomes. • Proton activated chloride channels are expressed in β cells. • Manipulation of PAC with overexpression and knockdown alters the amplitude of L type calcium currents and fast insulin release. • Manipulation of PAC with overexpression and knockdown alters entire insulin release under high glucose. • PAC affects key physiological parameters of Type II diabetic mouse model.

Source: The International Journal of Biochemistry & Cell Biology

DOI: 10.1016/j.biocel.2025.106879

Authors: Yi Wu, Fang Wang, Fang-Lin Peng

Institutions: Shanghai University of Medicine and Health Sciences, Eye & ENT Hospital of Fudan University

Language: English

Topic: Pancreatic function and diabetes

Subfield: Surgery

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,840