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HORMONES AND SIGNALING

Functional characterization and expression of PBR in rat gastric mucosa: stimulation of chloride secretion by PBR ligands

¹Institut National de la Santé et de la Recherche Médicale U410, Neuroendocrinologie et Biologie Cellulaire Digestives, 75870 Paris Cedex 18, France; ²Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, D.C. 20057; and ³Department of Cell Biology and Biochemistry, Texas Tech University Medical Center, Lubbock, Texas 79430

Submitted 10 July 2003 ; accepted in final form 7 January 2004

Previous studies have demonstrated that gastric mucosa contained high levels of the polypeptide diazepam binding inhibitor, the endogenous ligand of the peripheral-type benzodiazepine receptor (PBR). However, the expression and function of this receptor protein in these tissues have not been investigated. Immunohistochemistry identified an intense PBR immunoreactivity in the mucous and parietal cells of rat gastric fundus and in the mucous cells of antrum. Immunoelectron microscopy revealed the mitochondrial localization of PBR in these cells. Binding of isoquinoline PK 11195 and benzodiazepine Ro5–4864 to gastric membranes showed that fundus had more PBR-binding sites than antrum, displaying higher affinity for PK 11195 than Ro5–4864. In a Ussing chamber, PK 11195 and Ro5–4864 increased short-circuit current (I_sc) in fundic and antral mucosa in a concentration-dependent manner in the presence of GABA_A and central benzodiazepine receptor (CBR) blockers. This increase in I_sc was abolished after external Cl^– substitution and was sensitive to chloride channels or transporter inhibitors. PK 11195-induced chloride secretion was also 1) sensitive to verapamil and extracellular calcium depletion, 2) blocked by thapsigargin and intracellular calcium depletion, and 3) abolished by the mitochondrial pore transition complex inhibitor cyclosporine A. PK 11195 had no direct effect on H⁺ secretion, indicating that it stimulates a component of Cl^– secretion independent of acid secretion in fundic mucosa. These data demonstrate that mucous and parietal cells of the gastric mucosa express mitochondrial PBR functionally coupled to Ca²⁺-dependent Cl^– secretion, possibly involved in the gastric mucosa protection.

mitochondria; PK 11195; Ro5–4864; diazepam

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