The identification of the biological functions of TRP (transient receptor potential) proteins requires genetic approaches because a selective TRP channel pharmacology to unravel the roles of TRPs is not available so far for most TRPs. A survey is therefore presented of transgenic animal models carrying mutations in TRP genes, as well as of those TRP genes that when mutated result in human disease; the chromosomal locations of TRP channel genes in the human and mouse are also presented.
- genetic disease
- knockout animal
- spontaneous mutation
- transgenic animal
- transient receptor potential gene (TRP gene)
- transient receptor potential melastatin 8 (TRPM8)
The identification of the biological functions of the heterogeneous family of TRP (transient receptor potential) proteins is of paramount importance, especially because a selective TRP channel pharmacology to unravel roles of TRP channels does not exist so far. The best compounds, both blocking and activating, are available for TRPV1 (TRP vanilloid 1) and TRPM8 (TRP melastatin 8). Both channels are prototypes of the thermoTRPs, a subset of TRPs that are activated by distinct temperatures and are involved in converting thermal information into chemical and electrical signals. Genetic approaches, in worms, flies and mice demonstrate a role for many TRP proteins in an assortment of sensory processes ranging from thermosensation to osmosensation, olfaction, taste, mechanosensation, vision and pain perception. Several recent studies have begun to unravel roles for TRP proteins in non-excitable cells, including a requirement in endothelium-dependent vasorelaxation and smooth-muscle-dependent contractility, as indicated by analyses of TRPC4 (TRP canonical 4)- and TRPC6-knockout mice (Table 1). These mouse models and further examination of how the mutant animal differs from normal, and when it begins to differ from normal, will surely be of aid in providing information of further and novel TRP functions.
At the same time it will be possible to create transgenic animals with mutations in TRP genes which in humans have been linked to disease. Analysis of these mouse models will help to investigate the role of those mutated genes in depth and their interaction with other genes in the living organism. To date, mutations in five different TRPs have been linked to human disease (Table 2), whereas expression of several TRPs correlates with cell proliferation and tumour progression. Furthermore, TRPM1 has been suggested to be a tumour suppressor, and a decrease in expression of TRPM1 appears to be a prognostic marker for metastasis in patients with localized malignant melanoma. In addition, expression of TRPM8 and TRPV6 appears to be up-regulated in prostate cancers and may represent new diagnostic markers for that disease. TRPM8 is also up-regulated in cancers of lung, breast and skin.
At present we are still at the very beginning of understanding the impact of TRP genes on very diverse cell and organ functions and their roles in disease. TRP pharmacology is still not at an advanced stage, with the exceptions indicated above, but one of the main challenges in this field will be to define in more detail physiological TRP channel functions and properties of TRP channels as targets for novel drugs. Transgenic mouse models and their analysis will prove to be essential to attain this goal.
Cell and Molecular Biology of TRP Channels: Biochemical Society Focused Meeting held at University of Bath, U.K., 7–8 September 2006. Organized and Edited by D. Beech (Leeds, U.K.), B. Reaves (Bath, U.K.) and A. Wolstenholme (Bath, U.K.).
Abbreviations: CT, chorda tympani; TRP, transient receptor potential; TRPC, TRP canonical; TRPM, TRP melastatin; TRPV, TRP vanilloid
- © 2007 The Biochemical Society