Physiology, Phylogeny, and Functions of the TRP Superfamily of Cation Channels

The transient receptor potential (TRP) protein superfamily consists of a diverse group of Ca2+ permeable nonselective cation channels that bear structural similarities to Drosophila TRP. TRP-related proteins play important roles in nonexcitable cells, as demonstrated by the recent finding that a mammalian TRPC protein is expressed in endothelial cells and functions in vasorelaxation. However, an emerging theme is that many TRP-related proteins are expressed predominantly in the nervous system and function in sensory physiology. The TRP superfamily can be divided into six subfamilies, the first of which is composed of the "classical TRPs" (TRPC subfamily). These proteins all share the common features of three to four ankryin repeats, ≥30% amino acid homology over ≥750 amino acids, and a gating mechanism that operates through phospholipase C. Some classical TRPs may be store-operated channels (SOCs), which are activated by release of Ca2+ from internal stores. The mammalian TRPC proteins are also expressed in the central nervous system, and several are highly enriched in the brain. One TRPC protein has been implicated in the pheromone response. The archetypal TRP, Drosophila TRP, is predominantly expressed in the visual system and is required for phototransduction. Many members of a second subfamily (TRPV) function in sensory physiology. These include VR1 and OSM-9, which respond to heat, osmolarity, odorants, and mechanical stimuli. A third subfamily, TRPN, includes proteins with many ankyrin repeats, one of which, NOMPC, participates in mechanotransduction. Among the members of a fourth subfamily, TRPM, is a putative tumor suppressor termed melastatin, and a bifunctional protein, TRP-PLIK, consisting of a TRPM channel fused to a protein kinase. PKD2 and mucolipidin are the founding members of the TRPP and TRPML subfamilies, respectively. Mutations in PKD2 are responsible for polycystic kidney disease, and mutations in mucolipidin result in a severe neurodegenerative disorder. Recent studies suggest that alterations in the activities of SOC and TRP channels may be at the heart of several additional neurodegenerative diseases. Thus, TRP channels may prove to be important new targets for drug discovery. The Drosophila transient receptor potential (trp) locus was discovered more than 30 years ago on the basis of its critical role in visual transduction. For many years, the molecular identity and function of the TRP protein were enigmatic. However, recent studies indicate that TRP is the defining member of large superfamily of Ca2+-permeable cation channels that are conserved from worms to humans. Members of the TRP superfamily function in a variety of critical processes such as phototransduction, mechanotransduction, pain perception, osmosensation, and vasorelaxation. In addition, the mechanisms underlying the activation of these cation channels are diverse. Some appear to be receptor-operated channels, whereas others appear to be gated by changes in osmolarity, pH, or temperature. Lastly, investigations into the functions and modes of activation of TRP-related proteins have relevance for human health, because mutations in at least two members of the TRP superfamily are responsible for human diseases.