Regulation of TRPV5 and TRPV6 by associated proteins

Abstract

The epithelial Ca 2ϩ channels TRPV5 and TRPV6 are the most Ca 2ϩ -selective members of the TRP channel superfamily. These channels are the prime target for hormonal control of the active Ca 2ϩ flux from the urine space or intestinal lumen to the blood compartment. Insight into their regulation is, therefore, pivotal in our understanding of the (patho)physiology of Ca 2ϩ homeostasis. The recent elucidation of TRPV5/ 6-associated proteins has provided new insight into the molecular mechanisms underlying the regulation of these channels. In this review, we describe the various means of TRPV5/6 regulation, the role of channel-associated proteins herein, and the relationship between both processes. Rab11; calbindin; 80KH; BSPRY; Klotho; kidney TRANSCELLULAR Ca 2ϩ (re)absorption is a pivotal process in the maintenance of extracellular Ca 2ϩ balance. It allows the organism to respond to fluctuations in dietary Ca 2ϩ and adapt to the body's demand during processes such as growth, pregnancy, lactation, and aging. The first step in transcellular transport is the influx of Ca 2ϩ across the apical membrane of the epithelial cell, which is a tightly controlled mechanism (Fig. 1). Next, Ca 2ϩ enters the cell and is sequestered by specialized proteins called calbindins to maintain low cytosolic Ca 2ϩ concentrations. Subsequently, bound Ca 2ϩ diffuses to the basolateral side of the cell, where it is extruded into the bloodstream via the Na ϩ /Ca 2ϩ exchanger (NCX1) and plasma membrane Ca 2ϩ -ATPase (PMCA1b). The molecular identification of two members of the transient receptor potential (TRP) superfamily, TRPV5 (28) and TRPV6 (48), boosted the research addressing the molecular mechanism of epithelial Ca 2ϩ transport. The physiological role of these channels has been substantiated in several mouse models of Ca 2ϩ -related disorders, including vitamin D deficiency rickets type I (VDDR-I) (13, 25) and vitamin D-resistant rickets type II (60) (VDDR-II). Furthermore, TRPV5 (29) and TRPV6 (3) knockout mice show significant disturbances in their Ca 2ϩ homeostasis. TRPV5 primarily fulfills the role as gatekeeper of epithelial Ca 2ϩ transport in the kidney (27), whereas TRPV6 forms the main Ca 2ϩ influx pathway in the small intestine (41). Therefore, detailed insight into the molecular regulation of TRPV5/6 is pivotal to our understanding of Ca 2ϩ homeostasis. STRUCTURAL FEATURES OF TRPV5 AND TRPV6TRPV5 and TRPV6 display the highest sequence homology with the vanilloid receptor subfamily (TRPV) of TRP channels. These channels share a predicated topology consisting of large intracellular NH 2 -and COOH-terminal tails flanking six transmembrane segments (TM) and an additional hydrophobic stretch between TM5 and TM6, forming the pore-forming region (Fig. 2). Several TRP channels contain ankyrin repeats in their NH 2 terminus. The number of ankyrin repeats range from 0 to 14, and the members of the TRPV subfamily have 3-4 repeats (12), varying slightly depending on the sequencesimilarity algorithm used. TRPV5 and TRPV6 display several prope...

Excision of Trpv6 Gene Leads to Severe Defects in Epididymal Ca2+ Absorption and Male Fertility Much Like Single D541A Pore Mutation

“…mice, we could not exclude residual channel activity of the properly expressed and trafficked, yet mutated TRPV6 D541A proteins, which might in addition serve channel-independent functions as structural and/or scaffolding components (19) of the epithelial plasma membrane. Thus, the TRPV6 D541A mutation might not be sufficient to identify all TRPV6-related functions, and it is conceivable that a complete loss of TRPV6 proteins leads to additional phenotypes.…”

Annexin A2 Mediates Apical Trafficking of Renal Na+-K+-2Cl− Cotransporter

“…Subsequent ranking of the candidates by their renal expression levels identified AnxA2 as the product with the strongest expression in rat and human TAL. Because annexins may serve as trafficking factors for various transmem- brane proteins (29,(53)(54)(55), we hypothesized that AnxA2 may be involved in the trafficking of NKCC2.…”

A Protein Interaction Network for the Large Conductance Ca2+-activated K+ Channel in the Mouse Cochlea

“…It may attach to the BK EF-hand domain, as annexins have a binding affinity for EF-hand Ca 2ϩ -binding proteins. However, with channels such as TRP and TASK-1 the link occurs via an annexin subunit/ complex known by the various names of S100A10/p11/annexin II light chain (37,38). Of particular interest, in this dynamic, is that apolipoprotein binds to annexins in a Ca 2ϩ -dependent manner (39).…”