The TRP superfamily includes > 20 related cation channels that play critical roles in processes ranging from sensory physiology to vasorelaxation and altered sexual and social behaviours. Defects in TRP channels have been associated with changes in growth control, and other TRP-related proteins appear to be prognostic markers for metastasis in patients with localized malignant melanoma and the progression in prostatic cancer. TRP proteins are widely expressed in the nervous system, and, in non-excitable cells, TRP-related channels may be the primary mode of Ca entry. TRP proteins are cation channels; however, they vary significantly in their selectivity and mode of activation. In addition, at least one of these channel proteins, PKD2 or TRPP2, appears to be a endoplasmic reticulum Ca release channel. Nevertheless, members of the TRP superfamily share significant sequence homology and predicted structural similarities, such as six predicted transmembrane segments.

The current focus of our work is on TRPC4, a member of the TRPC subfamily, and on TRPV6 (formerly called CaT-like), a member of the TRPV subfamily. TRPC4 has been implicated in store-operated Ca-entry in various cells and endothelial cells – both macrovascular and microvascular – of mice deficient in TRPC4 lack a store-operated Ca current. As a consequence, agonist-induced Ca entry and vasorelaxation is reduced markedly, showing that TRPC4 is an indispensable component of store-operated channels in native endothelial cells and that these channels directly provide a Ca-entry pathway essentially contributing to blood vessel tone and microvascular endothelial permeability. The TRPC4 protein contains three binding sites for Ca-calmodulin and is part of a signalling complex, which also contains phospholipase C and is assembled by the divalent PDZ-domain protein NHERF (synonym ezrin binding protein 50).

TRPV6 is abundantly expressed in acinar cells of the pancreas, myoepithelial cells of the salivary gland and trophoblasts and syncytiotrophoblasts of the placenta. It encodes a cation channel which is highly Ca selective. TRPV6 is also expressed in locally advanced prostate cancer, metastatic and androgen-insensitive prostatic lesions, but is undetectable in healthy prostate tissue and benign prostatic hyperplasia. Accordingly, a molecular classification of prostate cancer subclasses and class prediction by monitoring the level of human TRPV6 gene expression may be feasable. In addition, the TRPV6 channel may serve as a target for therapeutic strategies in cancer treatment.

This work was supported by the Deutsche Forschungsgemeinschaft and Fonds der Chemischen Industrie.