Transient Receptor Potential (TRP) cation channels are unique cell sensors responding to a plethora of gating stimuli. The TRP superfamily comprises in human 27 mammalian cation channels subdivided into six subfamilies: TRPC ('Canonical'), TRPV ('Vanilloid'), TRPM ('Melastatin'), TRPP ('Polycystin'), TRPML ('Mucolipin') and the TRPA ('Ankyrin') groups. In a first part, the diversity of TRP channel gating and permeation properties will be shortly reviewed. The question why TRP channels seem to be so special regarding the multiple activation modes and cell functions will be elucidated by the example of the weakly voltage dependent TRP channels. It will be hypothesized that the small gating charge of most of the TRP channels might support dramatic shifts of voltage dependence due to several stimulating stimuli (4). In a second part, the function of three TRP channels, TRPM4, TRPM5, TRPV4, will be described and a link to diseases will be shown. TRPM4 and TRPM5 are Ca²⁺ activated non-selective cation channel modulated by phosphatidylinositol-phosphates. Although rather homologous, they differ in the Ca²⁺ and voltage dependence, their desensitization behavior due to PI(4,5)P₂ depletion and their expression pattern. TRPM4 deficient mice show increased adrenergic inotropic responses, develop heart hypertrophy and develop an increased blood pressure due to an increased catecholamine release from chromaffin cells. It will be also shown that TRPM4 plays some surprising role in synaptic plasticity in the central nervous system, including modulation of LTP in hippocampal neurons. TRPM5 is critically involved in insulin release. It will be demonstrated how TRPM5 fine-tunes insulin release and that knocking-down for TRPM5 causes a diabetes type 2 like phenotype. TRPV4 is considered as an indirectly mechano-sensitive channel. Like other TRPVs, the N terminus of TRPV4 contains 6 ankyrin repeats (ANK) that are linked by extraordinary long "finger-like" folds. A proline-rich domain (PRD) involved in mechanosensity of the TRPV4 channel locates close to ANK1. The central residues of PRD interact with PACSIN 3, a protein implicated in cytoskeleton reorganization. The expression pattern of TRPV4 is relatively broad. TRPV4 is highly expressed in the brain (hypothalamic structures). It has been found in motor, spinal ventral root and dorsal root ganglia neurons. Prominent TRPV4 locations are cartilage, bladder urothelium, kidney, vascular endothelium, pulmonary aortic smooth muscle and the inner ear. trpv4^-/- mice develop a mast-cell gain-of-function phenotype with altered migration and develop a distinct bladder phenotype. The voiding pattern is disturbed in trpv4^-/- mice, i.e. an atypical cystometric pattern is caused by a dysfunction of the mechano-sensor affecting stretch-induced release of ATP. The overactive bladder syndrome (OAB), which develops during cystitis, can be successfully treated with selective inhibitors of TRPV4. An osteoclast dysfunction causes in trpv4^-/-mice an increased bone mass. TRPV4 is required for the final differentiation of osteoclasts and is linked to osteoporosis. In a third part, TRP channelopathies will be discussed (3). Surprisingly, many mutations in TRPV4 have been discovered which lead mostly to gain-of-function phenotypes and are probably causative for several human diseases, such as bone diseases (brachyolmia, spondylometaphyseal dysplasia, metatropic dysplasia, spondylo-epiphyseal dysplasia, Maroteaux, parastremmatic dyplasia) (2). Surprisingly, the scapuloperoneal spinal muscle atrophy and Charcot-Marie-Tooth disease type 2C, genetically heterogeneous inherited disorders caused by degeneration of peripheral nerves, also depend on TRPV4 (1). Some surprising dilemmas to explain different phenotypes by mutations in a narrow, e.g. ARD region, will be discussed. Finally, the role of the "chemosensory" TRPA1 channel in a pain syndrome will be evaluated and some unexpected roles of this channel in causing headache and migraine will be shown, as well as the dramatic involvement of TRPA1 in the development of neuropathic pain during tumor chemotherapy.

1. Nilius B, Owsianik G (2010) Channelopathies converge on TRPV4. Nature Genetics 42:98–100

2. Nilius B, Owsianik G (2010) Transient receptor potential channelopathies. Pflügers Archiv European Journal of Physiology 460:437–50

3. Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient Receptor Potential Channels in Disease. Physiol Rev. 87:165–217

4. Nilius B, Talavera K, Owsianik G, Prenen J, Droogmans G, Voets T (2005) Gating of TRP channels: a voltage connection? J Physiol. (Lond) 567:33–44