TRPV5PMCAMechanismus

The transient receptor potential vanilloid 5 (TRPV5) channel is a calcium-permeable ion channel primarily expressed in the distal nephron of the kidney, where it plays a critical role in calcium reabsorption. The TRPV5 protein contains six transmembrane domains, a pore loop, and intracellular N- and C-termini, with its activation tightly regulated to maintain calcium homeostasis. The mechanism by which TRPV5 is modulated involves a combination of direct gating by calcium and phosphorylation-dependent regulation, often mediated by protein kinases.

One key regulatory pathway involves the protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII). Upon activation by extracellular calcium or membrane depolarization, TRPV5 undergoes conformational changes that allow calcium influx. This influx can further activate intracellular signaling cascades, including PKC and CaMKII, which phosphorylate TRPV5 at specific serine and threonine residues. Phosphorylation enhances channel stability, surface expression, and open probability, thereby increasing calcium reabsorption efficiency.

Another layer of regulation is provided by the protein calmodulin (CaM), which binds to TRPV5 in a calcium-dependent manner. This binding can either inhibit or facilitate channel activity depending on intracellular calcium levels, acting as a feedback mechanism to prevent excessive calcium influx. Additionally, TRPV5 interacts with scaffolding proteins such as PDZ-domain-containing proteins, which influence its trafficking and localization within the plasma membrane.

Disruptions in TRPV5 regulation, such as mutations or altered expression, have been linked to conditions like hypocalcemia or hypercalciuria, underscoring its importance in renal calcium handling. Research continues to elucidate the precise molecular interactions governing TRPV5 function, with potential therapeutic implications for calcium-related disorders.