TRPV5 (transient receptor potential vanilloid) is a unique calcium-selective TRP channel that is essential for calcium homeostasis. TRPV5 and its close homologue TRPV6 do not exhibit thermosensitivity or ligand-dependent activation, unlike other TRPV channels, but are constitutively opened at physiological membrane potentials. Here, we report high resolution electron cryo-microscopy (cryo-EM) structures of truncated and full length TRPV5 in lipid nanodisc, as well as a TRPV5 W583A mutant structure and a complex structure of TRPV5 with calmodulin (CaM). These structures highlight and explain functional differences between the thermosensitive and calcium-selective TRPV channels. An extended S1-S2 linker folds on top of the channel that might shield it from modulation by extracellular factors. Resident lipid densities in the homologous vanilloid pocket are different from those previously found in TRPV1, supporting a comparatively more rigid architecture of TRPV5. A ring of tryptophan residues (W583) at the bottom of the pore coordinates a density and mutation of W583 resultes in opening of the lower gate. Moreover, we provide structural insight into the calcium-dependent channel inactivation and propose a flexible stoichiometry for TRPV5 and CaM binding.

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.

TRPV5 (transient receptor potential vanilloid 5) is a unique calcium-selective TRP channel essential for calcium homeostasis. Unlike other TRPV channels, TRPV5 and its close homolog, TRPV6, do not exhibit thermosensitivity or ligand-dependent activation but are constitutively open at physiological membrane potentials and modulated by calmodulin (CaM) in a calcium-dependent manner. Here we report high-resolution electron cryomicroscopy structures of truncated and full-length TRPV5 in lipid nanodiscs, as well as of a TRPV5 W583A mutant and TRPV5 in complex with CaM. These structures highlight the mechanism of calcium regulation and reveal a flexible stoichiometry of CaM binding to TRPV5.