Mensenkamp A R, Hoenderop J G J, Bindels R J M
Department of Physiology, Radboud University Nijmegen Medical Center, 286 Cell Physiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Handb Exp Pharmacol. 2007(179):207-20. doi: 10.1007/978-3-540-34891-7_12.
Ca2+ homeostasis in the body is tightly controlled, and is a balance between absorption in the intestine, excretion via the urine, and exchange from bone. Recently, the epithelial Ca2+ channel (TRPV5) has been identified as the gene responsible for the Ca2+ influx in epithelial cells of the renal distal convoluted tubule. TRPV5 is unique within the family of transient receptor potential (TRP) channels due to its high Ca2+ selectivity. Ca2+ flux through TRPV5 is controlled in three ways. First, TRPV5 gene expression is regulated by calciotropic hormones such as vitamin D3 and parathyroid hormone. Second, Ca2+ transport through TRPV5 is controlled by modulating channel activity. Intracellular Ca2+, for example, regulates channel activity by feedback inhibition. Third, TRPV5 is controlled by mobilization of the channel through trafficking toward the plasma membrane. The newly identified anti-aging hormone Klotho regulates TRPV5 by cleaving off sugar residues from the extracellular domain of the protein, resulting in a prolonged expression of TRPV5 at the plasma membrane. Inactivation of TRPV5 in mice leads to severe hypercalciuria, which is compensated by increased intestinal Ca2+ absorption due to augmented vitamin D3 levels. Furthermore, TRPV5 deficiency in mice is associated with polyuria, urine acidification, and reduced bone thickness. Some pharmaceutical compounds, such as the immunosuppressant FK506, affect the Ca2+ balance by modulating TRPV5 gene expression. This underlines the importance of elucidating the role of TRPV5 in Ca(2+)-related disorders, thereby enhancing the possibilities for pharmacological intervention. This chapter describes a unique TRP channel and highlights its regulation and function in renal Ca2+ reabsorption and overall Ca2+ homeostasis.
体内的钙离子稳态受到严格控制，是肠道吸收、尿液排泄以及骨钙交换之间的平衡。最近，上皮钙离子通道（TRPV5）已被确定为负责肾远曲小管上皮细胞钙离子内流的基因。TRPV5在瞬时受体电位（TRP）通道家族中具有独特性，因其对钙离子具有高选择性。通过TRPV5的钙离子通量受三种方式控制。首先，TRPV5基因表达受维生素D3和甲状旁腺激素等钙调节激素调控。其次，通过调节通道活性来控制钙离子通过TRPV5的转运。例如，细胞内钙离子通过反馈抑制调节通道活性。第三，TRPV5通过向质膜转运来控制通道的动员。新发现的抗衰老激素α-klotho通过从该蛋白的细胞外结构域切除糖基来调节TRPV5，从而导致TRPV5在质膜上的表达延长。小鼠中TRPV5失活会导致严重的高钙尿症，这可通过因维生素D3水平升高而增加的肠道钙离子吸收来补偿。此外，小鼠中TRPV5缺乏与多尿、尿液酸化和骨厚度降低有关。一些药物化合物，如免疫抑制剂FK506，通过调节TRPV5基因表达来影响钙离子平衡。这凸显了阐明TRPV5在与钙相关疾病中的作用的重要性，从而增加了药物干预的可能性。本章描述了一种独特的TRP通道，并强调了其在肾脏钙离子重吸收和整体钙离子稳态中的调节和功能。
