TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of TRPV5 and TRPV6

Abstract

Maintaining plasma calcium levels within a narrow range is of vital importance for many physiological functions. Therefore, calcium transport processes in the intestine, bone and kidney are tightly regulated to fine-tune the rate of absorption, storage and excretion. The TRPV5 and TRPV6 calcium channels are viewed as the gatekeepers of epithelial calcium transport. Several calciotropic hormones control the channels at the level of transcription, membrane expression, and function. Recent technological advances have provided the first near-atomic resolution structural models of several TRPV channels, allowing insight into their architecture. While this field is still in its infancy, it has increased our understanding of molecular channel regulation and holds great promise for future structure-function studies of these ion channels. This review will summarize the mechanisms that control the systemic calcium balance, as well as extrapolate structural views to the molecular functioning of TRPV5/6 channels in epithelial calcium transport.

Structural insight into TRPV5 channel function and modulation

“…Together with its close homolog TRPV6, they are also different from other members of the vanilloid subfamily (TRPV1-4) and are not considered to be thermosensitive or ligand-activated (2,3). Physiologically, TRPV5 and TRPV6 serve as apical entryways into epithelial cells that line parts of the gut and nephron, initiating transcellular calcium transport pathways that help fine-tune serum calcium levels (4). Disturbances in the body's calcium balance can cause major health problems, including neurological and cardiac aberrations, stone formation, and bone disorders.…”

Evolutionary analyses unveil the molecular mechanism of fast inactivation in calcium-permeable TRP channels

“…In vertebrates, epithelial calcium absorption is a crucial physiological process needed to maintain Ca 2+ homeostasis. Epithelia consist of a continuous layer of individual cells where calcium absorption is maintained by two routes, the transcellular and paracellular pathways (Goor et al, 2017;Hoenderop et al, 2005). Tight junctions regulate the passive passage of ions and molecules through the paracellular pathway .…”

“…Tight junctions regulate the passive passage of ions and molecules through the paracellular pathway . Calcium permeation through this pathway constitutes a major route for Ca 2+ absorption under normal physiological conditions (Goor et al, 2017). On the other hand, the transcellular pathway implicates controlled Ca 2+ movement through epithelial barriers and occurs against a concentration gradient in normal conditions.…”

“…On the other hand, the transcellular pathway implicates controlled Ca 2+ movement through epithelial barriers and occurs against a concentration gradient in normal conditions. It is an active and saturable process, maintained by an array of transporters, pumps, and ion channels (Goor et al, 2017).…”

Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM

“…In the absence of modulators, TRPV5 and TRPV6 are constitutively active channels 3 . Several endogenous modulators such as calmodulin and phosphatidylinositol 4,5-bisphosphate (PIP 2 ) have been found to stabilize these channels in the closed or open conformation, respectively 7,8 . Additionally, the small-molecule antifungals econazole and miconazole, which are commonly used topically to treat skin infections, have been shown to effectively inhibit both TRPV5 and TRPV6 (refs.…”