Structural basis of TRPV5 regulation by physiological and pathophysiological modulators.

ABSTRACT: Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca²⁺-selective ion channel that plays a key role in Ca²⁺ homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) and inhibition by Ca²⁺-bound calmodulin (CaM). Parathyroid hormone (PTH), the key extrinsic regulator of Ca²⁺ homeostasis, increases the activity of TRPV5 via protein kinase A (PKA)-mediated phosphorylation. Metabolic acidosis leads to reduced TRPV5 activity independent of PTH, causing hypercalciuria. Using cryoelectron microscopy (cryo-EM), we show that low pH inhibits TRPV5 by precluding PI(4,5)P₂ activation. We capture intermediate conformations at low pH, revealing a transi

SUBMITTER: Fluck EC 

PROVIDER: S-EPMC9088182 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature