Nikolovska Katerina, Seidler Ursula E, Stock Christian
Department of Gastroenterology, Hannover Medical School, Hannover, Germany.
Front Physiol. 2022 May 18;13:899286. doi: 10.3389/fphys.2022.899286. eCollection 2022.
The five plasma membrane Na/H exchanger (NHE) isoforms in the gastrointestinal tract are characterized by distinct cellular localization, tissue distribution, inhibitor sensitivities, and physiological regulation. NHE1 (Slc9a1) is ubiquitously expressed along the gastrointestinal tract in the basolateral membrane of enterocytes, but so far, an exclusive role for NHE1 in enterocyte physiology has remained elusive. NHE2 (Slc9a2) and NHE8 (Slc9a8) are apically expressed isoforms with ubiquitous distribution along the colonic crypt axis. They are involved in pH regulation of intestinal epithelial cells. Combined use of a knockout mouse model, intestinal organoid technology, and specific inhibitors revealed previously unrecognized actions of NHE2 and NHE8 in enterocyte proliferation and differentiation. NHE3 (Slc9a3), expressed in the apical membrane of differentiated intestinal epithelial cells, functions as the predominant nutrient-independent Na absorptive mechanism in the gut. The new selective NHE3 inhibitor (Tenapanor) allowed discovery of novel pathophysiological and drug-targetable NHE3 functions in cystic-fibrosis associated intestinal obstructions. NHE4, expressed in the basolateral membrane of parietal cells, is essential for parietal cell integrity and acid secretory function, through its role in cell volume regulation. This review focuses on the expression, regulation and activity of the five plasma membrane Na/H exchangers in the gastrointestinal tract, emphasizing their role in maintaining intestinal homeostasis, or their impact on disease pathogenesis. We point to major open questions in identifying NHE interacting partners in central cellular pathways and processes and the necessity of determining their physiological role in a system where their endogenous expression/activity is maintained, such as organoids derived from different parts of the gastrointestinal tract.
胃肠道中的五种质膜钠/氢交换体（NHE）亚型具有不同的细胞定位、组织分布、抑制剂敏感性和生理调节特性。NHE1（Slc9a1）在整个胃肠道的肠上皮细胞基底外侧膜中普遍表达，但迄今为止，NHE1在肠上皮细胞生理学中的独特作用仍不明确。NHE2（Slc9a2）和NHE8（Slc9a8）是顶端表达的亚型，沿结肠隐窝轴广泛分布。它们参与肠上皮细胞的pH调节。通过联合使用基因敲除小鼠模型、肠道类器官技术和特异性抑制剂，揭示了NHE2和NHE8在肠上皮细胞增殖和分化中以前未被认识的作用。NHE3（Slc9a3）表达于分化的肠上皮细胞顶端膜，是肠道中主要的非营养依赖性钠吸收机制。新型选择性NHE3抑制剂（替那帕诺）有助于发现囊性纤维化相关肠梗阻中新的病理生理和可药物靶向的NHE3功能。NHE4表达于壁细胞基底外侧膜，通过其在细胞体积调节中的作用，对壁细胞完整性和酸分泌功能至关重要。本综述重点关注胃肠道中五种质膜钠/氢交换体的表达、调节和活性，强调它们在维持肠道内环境稳定中的作用，或它们对疾病发病机制的影响。我们指出了在确定NHE在核心细胞途径和过程中的相互作用伙伴方面的主要开放性问题，以及在维持其内源表达/活性的系统（如源自胃肠道不同部位的类器官）中确定其生理作用的必要性。
