Ostuni M A, Marazova K, Peranzi G, Vidic B, Papadopoulos V, Ducroc R, Lacapere J-J
Institut National de la Santé et de la Recherche Médicale U410, Neuroendocrinologie et Biologie Cellulaire Digestives, 75870 Paris cedex 18, France.
Am J Physiol Gastrointest Liver Physiol. 2004 Jun;286(6):G1069-80. doi: 10.1152/ajpgi.00290.2003. Epub 2004 Jan 15.
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 Ca(2+)-dependent Cl(-) secretion, possibly involved in the gastric mucosa protection.
先前的研究表明，胃黏膜中含有高水平的多肽地西泮结合抑制剂，即外周型苯二氮䓬受体（PBR）的内源性配体。然而，该受体蛋白在这些组织中的表达和功能尚未得到研究。免疫组织化学鉴定出大鼠胃底的黏液细胞和壁细胞以及胃窦的黏液细胞中有强烈的PBR免疫反应性。免疫电子显微镜显示这些细胞中PBR定位于线粒体。异喹啉PK 11195和苯二氮䓬Ro5-4864与胃膜的结合表明，胃底的PBR结合位点比胃窦多，对PK 11195的亲和力高于Ro5-4864。在尤斯灌流室中，在存在γ-氨基丁酸A（GABA(A)）和中枢苯二氮䓬受体（CBR）阻滞剂的情况下，PK 11195和Ro5-4864以浓度依赖性方式增加胃底和胃窦黏膜的短路电流（I(sc)）。外部Cl(-)替代后，I(sc)的这种增加被消除，并且对氯离子通道或转运体抑制剂敏感。PK 11195诱导的氯离子分泌还：1）对维拉帕米和细胞外钙耗竭敏感，2）被毒胡萝卜素和细胞内钙耗竭阻断，3）被线粒体孔道转换复合物抑制剂环孢素A消除。PK 11195对H(+)分泌没有直接影响，表明它刺激了胃底黏膜中与酸分泌无关的氯离子分泌成分。这些数据表明，胃黏膜的黏液细胞和壁细胞表达与Ca(2+)依赖性Cl(-)分泌功能偶联的线粒体PBR，可能参与胃黏膜保护。
