PDF(Pubmed)
Abstract：
Cellular and organism survival depends upon the regulation of pH, which is regulated by highly specialized cell membrane transporters, the solute carriers (SLC) (For a comprehensive list of the solute carrier family members, see: https://www.bioparadigms.org/slc/ ). The SLC4 family of bicarbonate (HCO3-) transporters consists of ten members, sorted by their coupling to either sodium (NBCe1, NBCe2, NBCn1, NBCn2, NDCBE), chloride (AE1, AE2, AE3), or borate (BTR1). The ionic coupling of SLC4A9 (AE4) remains controversial. These SLC4 bicarbonate transporters may be controlled by cellular ionic gradients, cellular membrane voltage, and signaling molecules to maintain critical cellular and systemic pH (acid-base) balance. There are profound consequences when blood pH deviates even a small amount outside the normal range (7.35-7.45). Chiefly, Na+-coupled bicarbonate transporters (NCBT) control intracellular pH in nearly every living cell, maintaining the biological pH required for life. Additionally, NCBTs have important roles to regulate cell volume and maintain salt balance as well as absorption and secretion of acid-base equivalents. Due to their varied tissue expression, NCBTs have roles in pathophysiology, which become apparent in physiologic responses when their expression is reduced or genetically deleted. Variations in physiological pH are seen in a wide variety of conditions, from canonically acid-base related conditions to pathologies not necessarily associated with acid-base dysfunction such as cancer, glaucoma, or various neurological diseases. The membranous location of the SLC4 transporters as well as recent advances in discovering their structural biology makes them accessible and attractive as a druggable target in a disease context. The role of sodium-coupled bicarbonate transporters in such a large array of conditions illustrates the potential of treating a wide range of disease states by modifying function of these transporters, whether that be through inhibition or enhancement.
摘要：
细胞和生物体的生存取决于pH的调节，它由高度专业化的细胞膜转运蛋白调节，溶质载体(SLC)(有关溶质载体家族成员的全面列表，请参阅：https://www.bioparadigms.org/slc/)。碳酸氢盐（HCO3-）转运蛋白的SLC4家族由十个成员组成，通过它们与钠（NBCe1，NBCe2，NBCn1，NBCn2，NDCBE）的偶联来分类，氯化物（AE1，AE2，AE3），或硼酸盐（BTR1）。SLC4A9（AE4）的离子偶联仍存在争议。这些SLC4碳酸氢盐转运蛋白可能受细胞离子梯度控制，细胞膜电压，和信号分子，以维持关键的细胞和系统pH（酸碱）平衡。当血液pH值偏离正常范围（7.35-7.45）甚至少量时，都会产生深远的后果。主要是，钠偶联碳酸氢盐转运蛋白（NCBT）控制几乎每个活细胞的细胞内pH，维持生命所需的生物pH值。此外,NCBTs在调节细胞体积和维持盐平衡以及酸碱当量的吸收和分泌方面具有重要作用。由于它们不同的组织表达，NCBTs在病理生理学中发挥作用，当它们的表达减少或基因缺失时，它们在生理反应中变得明显。生理pH值的变化在各种条件下都可以看到，从典型的酸碱相关的病症到病理不一定与酸碱功能障碍相关，如癌症，青光眼,或各种神经系统疾病。SLC4转运蛋白的膜状位置以及在发现其结构生物学方面的最新进展使其作为疾病背景下的药物靶标可获得和有吸引力。钠偶联的碳酸氢盐转运体在如此大量的病症中的作用说明了通过改变这些转运体的功能来治疗多种疾病状态的潜力。无论是通过抑制还是增强。
