Could you close the door please? How calmodulin protects kidney cells from calcium toxicity

Calcium ions are actively reabsorbed over the kidney epithelial barrier, from the pro-urine back to the blood, in order to maintain a healthy whole-body calcium homeostasis. Transient Receptor Potential Vanilloid 5 (TRPV5) is an ion channel that facilitates the entry of calcium ions into the kidney cells, acting as a gatekeeper for the active calcium transport pathway. A high intracellular calcium concentration can cause cell death, therefore TRPV5-dependent calcium entry needs to be tightly controlled. Calmodulin plays an important role in a rapid negative feedback mechanism, acting as a calcium sensor that physically blocks the pore of TRPV5 when local calcium concentrations become dangerously high.

Malou Zuidscherwoude, Mark van Goor and colleagues (Dept. of Physiology, team of Joost Hoenderop) used a combination of biochemical and advanced microscopy techniques to come to a model of the dynamics of TRPV5 inactivation by calmodulin. The study, published in the Journal of Physiology, shows that calmodulin can already interact with TRPV5 in the absence of calcium. When calcium enters the cell, the interaction between calmodulin and TRPV5 increases which is dependent on the binding of calcium ions to one of the halves of calmodulin. Interestingly, the other half of calmodulin does not need to be calcified for effective inhibition of the TRPV5 channel. In addition, this study shows that the number of calmodulin molecules that interact with a TRPV5 channel increases upon calcium entry.

Transcellular calcium transport in the kidney is crucial for the fine-tuning of calcium concentrations in the blood. Disturbances in the body’s calcium homeostasis can lead to major health problems, including cardiac and neurological aberrations, kidney stone formation and bone disorders. The research group of Joost Hoenderop will continue to study the intricacies of TRPV5 regulation, currently focusing on the insertion of intracellularly stored calcium channels into the plasma membrane.

Publication in The Journal of Physiology

Functional basis for calmodulation of the TRPV5 calcium channel

Malou Zuidscherwoude, Mark K van Goor, Sara R Roig, Niky Thijssen, Merijn van Erp, Jack Fransen, Jenny van der Wijst, Joost G Hoenderop