TRPV5 and TRPV6 Calcium-Selective Channels

The epithelial calcium (Ca) channels TRPV5 and TRPV6 are members of the transient receptor potential (TRP) channel family TRPV (“V” for vanilloid) subgroup. TRPV5 and TRPV6 play major roles in the maintenance of blood Ca levels in higher organisms. Both channels exhibit similarities in many ways, as they share a high level (75%) of amino acid identity, comparable functional properties, and similar mechanisms of regulation. Also, they were discovered using similar cloning strategies [1,2]. Yet, their physiological contributions toward maintaining a systemic calcium balance are distinct. In addition, the following three key features distinguish TRPV5 and TRPV6 from other members of the TRP superfamily of cation channels: (1) high selectivity for Ca over other cations, (2) apical membrane localization in Ca-transporting epithelial tissues, and (3) responsiveness to 1,25-dihydroxyvitamin D (1,25[OH]D) [3,4]. These features make TRPV5 and TRPV6 ideally suited to facilitate intestinal absorption and renal reabsorption of Ca, serving as apical Ca entry channels in transepithelial Ca transport [5,6]. A major difference between the properties of TRPV5 and TRPV6 lies in their tissue distribution: TRPV5 is predominantly expressed in the distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, with limited expression in extrarenal tissues [1,7]. In contrast, TRPV6 exhibits a broader expression pattern, showing prominent expression in the intestine with additional expression in the kidney [8–10], placenta, epididymis, exocrine tissues (i.e., pancreas, prostate, salivary gland, sweat gland), and a few other tissues [11–13]. Thus, while TRPV5 plays a key role in determining the level of urinary Ca excretion, the physiological roles of TRPV6 are not limited to intestinal Ca absorption. Much progress has recently been made in understanding the roles of TRPV5 and TRPV6 channels in the kidney [14], intestine [15], placenta [16], and epididymis [17]. However, their roles in other organs have as yet not been fully investigated. In this chapter, we review the current status of our knowledge of the physiological and pathological roles of TRPV5 and TRPV6 and discuss a variety of techniques that have led to a deeper understanding of these channels. We review the identification strategies of TRPV5 and TRPV6 in searches for Ca absorption channels, as well as specific techniques used to reveal their key features. These include radiotracer Ca uptake and electrophysiology procedures, structure-function studies, methods to identify regulatory interacting partners, genetically engineered animals, strategies to study the role of TRPV6 in cancers, procedures for the development of small-molecule modulators of TRPV6 and TRPV5, the evaluation of variations/mutations in humans, and 3D structural determination. For additional information about TRPV5 and TRPV6, we would like to refer the interested reader to other comprehensive review articles [3–6,18].