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Gastric Proton Pumpopathy Associated with Protein Sorting Machinery: A Narrative Review
Aime Patrick Niyomugabo1, Leopold Ntakirutimana1, Jean Claude Habineza1
1Department of Physiology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Huye, Rwanda.
Background:
Gastric acid secretion by parietal cells depends on the trafficking and exocytosis of H⁺/K⁺-ATPase-rich tubulovesicles (TVs) to the apical membrane in response to histamine stimulation via cyclic AMP elevation. However, the role of parietal cell's protein sorting machinery [eg, coat protein (COP) II/COP I vesicle proteins, soluble NSF attachment protein receptors (SNAREs), Rab GTPases, clathrin-adaptor proteins, etc.] in the dysregulation of gastric acid homeostasis remains poorly understood. This review synthesizes available evidence on the role of protein sorting machinery in gastric proton pumpopathy, leading to dysregulation of gastric acid secretion.
Methods:
A thorough search was conducted on PubMed, with Wiley and African Journal Online as supplementary sources, and 15 original research articles published between January 1988 and July 2025 in English were included.
Results:
Misfolding of α- and β-subunits within the endoplasmic reticulum (ER) results in retention and degradation of the pump, leading to impaired acid secretion. Defective coat protein (COP) II/I vesicular transport disrupts Golgi processing and slows the delivery of proton pumps to tubulovesicles, while impaired Rab GTPase activity interferes with vesicle targeting toward the apical canalicular membrane. Also, dysregulation of SNARE complexes and adaptor proteins prevents effective vesicle docking and fusion, further compromising membrane insertion. In addition, abnormalities in endosomal recycling pathways hinder the retrieval and reinsertion of proton pumps, destabilizing long-term acid secretion.
Conclusion:
Defects in sorting machinery lead to gastric proton pumpopathy, causing impaired acid secretion. Thus, protein sorting regulators represent promising therapeutic targets to restore proper pump localization, which is a paradigm shift toward disease-modifying therapies that act upstream of the pump, potentially offering solutions for proton pump inhibitor (PPI)-resistant cases and congenital gastric acid disorders.
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