TRP channels: novel gating properties and physiological functions

This issue of The Journal of Physiology presents reports from a series of lectures given at the IUPS Syposium 2005 in San Diego on the transient receptor potential (TRP) channels. The plan of the organizers was to include a group of researchers into this novel and exciting superfamily of cation channels whose work combines basic biophysical and fundamental properties with specific cell and organ functions. Without doubt the TRP family of ion channels, which now comprises 28 mammalian members, have an extraordinarily important role as multifunctional cell sensors. Most of these channels are permeable to Ca2+, and some also to Mg2+. Only two members, so far, are Ca2+ impermeable but play an obviously important role by regulating the inward driving force for Ca2+ in many cell types. On the basis of sequence homology, the TRP family can be divided into seven main subfamilies: the TRPC (‘Canonical’) family, the TRPV (‘Vanilloid’) family, the TRPM (‘Melastatin’) family, the TRPP (‘Polycystin’) family, the TRPML (‘MucoLipin’) family, the TRPA (‘Ankyrin’) family, and the TRPN (‘NOMPC’) family. Our knowledge of these channels, which were first identified in Drosophila melanogaster as light-activated ion channels, has dramatically increased during the last five years through cloning and characterization in yeast, flies, worms, zebra fish and mammals. Typically, TRP channels are characterized by an impressive gating promiscuity, e.g. they are activated by a plethora of chemical and physical stimuli. Sensing such a wide range of stimuli allows them to effectively sense extra- and intracellular signals, which allows them to play a key role in processes which are important for the perception of light, taste compounds, olfactants and mechano (tactile) stimuli, e.g. sound detection. Importantly, some of these TRP channels are involved in life-threatening human diseases such as mucolipidosis IV, polycystic kidney disease, hypomagnesaemia with secondary hypocalcaemia, glomerulosclerosis and many others. This issue of The Journal of Physiology reports first on unexpected and novel properties of TRP channels, their voltage dependence (Nilius et al. 2005). These channels have been considered for a long time as typical voltage-independent channels which are mainly functional in non-excitable cells. Now, convincing evidence has been published that several TRP channels appear to be weakly voltage dependent. This weak voltage dependence (the moved gating charge is much lower than for the classical voltage-dependent Ca2+, K+ and Na+ channels) causes the activation curve to extend into the aphysiological positive voltage range. However, many physical stimuli, such as temperature (for TRPV1, TRPM8, TRPV3), or the binding of various ligands (for TRPV1, TRPV3, TRPM8, TRPM4) are able to shift this voltage dependence dramatically in the direction of negative potentials, and thus into the physiologically meaningful range. This is an unexpected gating principle and may represent the main functional hallmark of these TRP channels. The first review (Nilius et al. 2005) discusses this novel gating principle and gives some examples for dramatic shifts of TRPM4, TRPM8 and TRPV1 channels along the voltage axis toward negative potentials, and includes some structural considerations which might be helpful to further unravel the voltage sensing mechanism in TRP channels. Interestingly, one could imagine that the blueprint of weakly voltage-dependent channels might be an important principle in the evolution of multifunctional cell sensors. The second paper gives an intriguing example of the functional role of TRP channels in sensory physiology in the model system Drosophila, going back to the TRP roots (Montell, 2005). Indeed, the founding member of the TRPC subfamily, drosophilaTRP, is necessary for phototransduction. The Drosophila TRP channels are an intriguing example of the interaction of a channel with several proteins which together form a ‘signalplex’, whose intactness is required for a correctly working transduction of the perceived light signal. The Drosophila TRP channel, a channel belonging to the above defined TRPC family, forms together with two other TRPC channels, TRPL and TRPγ, heteromultimers with TRP. The whole signalplex includes the PDZ scaffold protein, INAD (inactivation, no after potential). INAD further binds a protein kinase C and a phospholipase C. Non-constitutive binding partners are the rhodopsin receptor, TRPL, the NINAC myosin III and calmodulin. Importantly, the Ca2+-permeable TRP channel also has non-channel functions and is necessary for anchoring INAD in the rhabdomers. TRPL (TRP-like), another Drosophila TRPC member, is translocated in a light-dependent manner and is actively involved in the light-sensing process. This is a fascinating comprehensive description of a signalplex, which might be a model for complex protein–protein interactions, which are expected for mammalian TRP channels. Intriguingly, Montell shows that loss of TRP function or constitutive activity results in retina degeneration, which is likely to be caused be a Ca2+ overload of the photoreceptor cell, a nice example and model system for the involvement of TRP channels in causing disease. Liedtke (2005) describes the function of a member of the vanilloid TRP subfamily, TRPV4. This channel is activated by a plethora of stimuli, including heat, specific ligands, such as 4αPDD, and lipids such as arachidonic acid and anadamide, which must be metabolized to epoxyeicosatrienoic acids (EETs). Importantly, TRPV4 is also activated by osmotic and mechanical stimuli and has been therefore considered as an osmo- and mechanosensor channel. Liedtke has developed a trpv4 null mouse. He shows that TRPV4 is necessary for stabilization of the osmotic equilibrium, for the drinking behaviour of mice and for normal thresholds in response to noxious mechanical stimuli. In an exciting genetic approach, Liedtke (2005) describes that in the worm Caenorhabditis elegans the phenotype of the TRPV mutant can be rescued by the mammalian TRPV4 and the mammalian transgene is directing the osmotic and mechanical avoidance response in ‘nociceptive’ neurones. This again is an exciting example of the functional role of TRP channels in complex systemic homeostasis but also in sensory mechanosensing. However, we still lack any clear mechanism for how this channel may measure mechanical forces and what the basic mechanism is for mechanosensing. The best-described mechanism so far is the coupling of TRPV4 with a mechanosensitive phospholipase A and channel activation by the arachidonic acid derived EET metabolites. To approach the complex role of mammalian TRPCs, Freichel et al. (2005) report on the well-known functional coupling of these channels with the PLC system. However, they now add some very striking examples of roles of these canonical TRP channels which have come as a real surprise. TRPC1 has now been identified as a mechanosensitive TRP channel rather than one just regulated via PLC. Another important TRPC role is the functional coupling with other ion channels by exchanging electrical signals. The review of Freichel et al. gives nice examples of the assignment of TRPC channels to various important cell functions such as axon guidance during brain development; the regulation, at least in mice, of sex recognition and social behaviour; and, in endothelial cell physiology, endothelium-dependent vasorelaxation and modulation of the paracellular barrier function. This reveiw includes also a discussion of one of the most recent findings on a ‘gain of function’ channelopathy of TRPC6 in the regulation of podocyte function in the glomerular filter, which causes focal and segmental glomerulosclerosis (FSGS). This short series of papers on TRP channel function will hopefully tempt the interested reader to enter the really exciting world of TRP channels and provide some guidance through this plethora of truly remarkable proteins.