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TRP Channels in Mechanosensation: Direct Or Indirect Activation?

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TRP Channels in Mechanosensation: Direct Or Indirect Activation? REVIEWS TRP channels in mechanosensation: direct or indirect activation? Adam P. Christensen and David P. Corey Abstract | Ion channels of the transient receptor potential (TRP) superfamily are involved in a wide variety of neural signalling processes, most prominently in sensory receptor cells. They are essential for mechanosensation in systems ranging from fruitfly hearing, to nematode touch, to mouse mechanical pain. However, it is unclear in many instances whether a TRP channel directly transduces the mechanical stimulus or is part of a downstream signalling pathway. Here, we propose criteria for establishing direct mechanical activation of ion channels and review these criteria in a number of mechanosensory systems in which TRP channels are involved. Osmoregulation Mechanically sensitive ion channels mediate a vast array — sensing force and passing the receptor current — or A homeostatic mechanism by of different cellular and organismic sensations, ranging does it have a necessary, but indirect, supporting role? which cells maintain their from the most basic that must occur in all living cells, Here we review the current literature using a set of criteria volume despite changes in such as osmoregulation, to the highly specialized, such designed to determine whether a candidate ion channel extracellular osmolarity. as hearing and touch. The channels that mediate these is directly activated by mechanical stimuli. Not all crite- sensations and how they convert a force stimulus ria can be met in all systems, so adequate proof in each into channel gating have remained largely a mystery. system may comprise satisfying only a subset of these Members of the transient receptor potential (TRP) family criteria. However, we hope that these criteria will help of ion channels have been implicated in a wide variety focus research in mechanosensation specifically for TRP of mechanical transduction processes in diverse organs channels and also, more generally, for all mechanically and species. sensitive ion channels. There are 33 TRP channel genes in mammals (nearly 60 in zebrafish, 30 in sea squirts, 24 in nematodes, 16 in Criteria to establish direct mechanical activation fruitflies and 1 in yeast)1. They are subdivided into seven In evaluating a mechanosensory system, we need to subfamilies on the basis of sequence similarity1 (FIG. 1). ask whether the receptor current is carried by an ion The channel subunits they encode have a molecular channel that is directly activated by the stimulus, and architecture similar to that of members of the voltage- whether a particular candidate protein participates in gated ion channel superfamily: they all include at least six that channel. transmembrane domains, as well as a number of other domains (FIG. 2), and four subunits assemble to form a Does mechanosensation involve direct activation of a functional ion channel. We will use the subunit name channel? Several tests may distinguish between mechani- to refer also to the channel it forms as a homotetramer. cally gated channels that act as force sensors themselves Some TRP channel subunits can form heterotetrameric and mechanically sensitive channels that are activated by channels as well, giving rise to a large variety of channels second messengers downstream of the true force sensors. with different gating and permeability properties2. Most First, the latency of the current elicited by the stimulus TRP channels are non-selective cation channels3. In addi- should be faster than known second-messenger systems, Department of Neurobiology, Harvard Medical School, tion to mechanosensation, TRP channels are involved in typically less than 5 milliseconds. Currently, many of the 220 Longwood Avenue, the transduction of a wide variety of other sensations, stimuli used to demonstrate mechanosensitivity, particu- Boston, Massachusetts with roles in vision, olfaction, taste, chemosensation and larly osmotic stimuli, lack the rapid risetime needed to 02115, USA. thermosensation4,5. determine a latency that is this fast. Second, the kinetics Correspondence to A.P.C. e-mail: However, the specific function of these, and other, ion of channel activation should depend on the amplitude of [email protected] channels in the process of mechanosensation is not fully the stimulus — a larger mechanical force should result doi:10.1038/nrn2149 understood6. Is the ion channel the primary transducer in faster channel opening. This is a simple consequence 510 | JULY 2007 | VOLUME 8 www.nature.com/reviews/neuro © 2007 Nature Publishing Group REVIEWS Mouse mmTRPM7 Frog mmTRPM6 Nematode mmTRPM3 mmTRPM8 Yeast mmTRPM1 dmNOMPC mmTRPM2 Fly mmTRPM4 (TRPN1) mmTRPM5 dm painless ceNOMPC dmTRP xINOMPC dmTRPL mmTRPC1 TRPM mmTRPC4 TRPN mmTRPC5 mmTRPA1 mmTRPC6 mmTRPML3 mmTRPC3 mmTRPML2 TRPA TRPC mmTRPC7 mmTRPC2 mmTRPML1 mmTRPV1 TRPML TRPV mmTRPV2 TRPP scTRPY1 ceLOV-1 mmTRPV3 mmTRPV4 mmPKD-REJ mmTRPV5 mmPKD2 (TRPP2) mmPKD2L2 mmTRPV6 ceOCR-3 mmPKD1 mmPKD1L2 mmPKD2L1 (TRPP5) (TRPP1) (TRPP3) dm inactive ceOCR-1 cePKD-2 ceOSM-9 ceOCR-2 mmPKD1L1 mmPKD1L3 dm nanchung ceOCR-4 (TRPP4) Figure 1 | Phylogeny of representative TRP channels. A phylogenic tree was generated in ClustalX by aligning the transmembrane domains of all 33 transient receptor potential (TRP) channels from mouse and some from other species. The seven main branches are denoted by circles at the branch roots. The letters and numbers following TRP denote TRP subfamily and member, respectively. Different species are indicated by colours and by prefixes. ce, Caenorhabditis elegans; dm, Drosophila melanogaster; mm, Mus musculus; sc, Saccharomyces cerevisiae; xl, Xenopus laevis. Scale bar represents 0.2 nucleotide substitutions per site. of a larger force lowering the energy barrier to channel Is the candidate protein mechanically sensitive? If a opening. Finally, there should be a mechanical correlate channel is directly activated by a mechanical stimulus of channel gating, such as an observable movement or then it should retain this mechanical gating property change in mechanical force, in the sensory cell or organ when expressed in other cells (as long as the force over the same range of stimuli as opens the channel. For stimulus is applied in an appropriate manner). For force to open a channel, some part of the channel or an example, if a channel operates by directly sensing lipid associated subunit that is closely coupled to the gating has tension, then the recombinant protein should retain its to move in response to force and this movement can be ability to be opened by pressure stimuli when placed detectable. This correlate will vary with differing gating in liposomes. Furthermore, in a heterologous expres- mechanisms (BOX 1) and might be difficult to measure sion system the forces necessary to gate the candidate but, when present, it is strong evidence for direct gating. channel should be comparable to the physiological This criterion, of course, addresses only the mode of stimulus. However, it should be noted that, if force is activation of the channel and not its molecular identity. conveyed to a channel by structural proteins that are present only in the receptor cell, or if required lipids Liposome A lipid vesicle that is artificially Does the candidate protein participate in mechanical or cofactors are present only in the receptor cell, acti- formed by sonicating lipids in transduction? To be a reasonable candidate for trans- vation in a heterologous expression system might be an aqueous solution. ducing the mechanosensory stimulus, a channel protein more difficult. must be in the right place and must be necessary for Heterologous expression mechanotransduction. Thus, the candidate channel Is the candidate protein a pore-forming subunit? Even system A system for studying the gene must be expressed in the receptor cell by the time if expressed at the right time and place, a candidate function of a protein in which a during development that the mechanically sensitive protein could be an accessory protein for the channel gene construct is transfected current is detected. The candidate channel protein but not part of the ion conduction pathway. If the can- into suitable host cells such as should be located at the site of mechanical transduc- didate protein forms the ion channel pore, the pharma- bacteria or cultured mammalian cells that will tion within the cell. Finally, blocking candidate protein cology and permeation properties of the mechanically produce the protein in a near- expression by knockdown or knockout should block the gated conductance in sensory cells should be similar native environment. mechanically activated conductance. to those of the heterologously expressed candidate. NATURE REVIEWS | NEUROSCIENCE VOLUME 8 | JULY 2007 | 511 © 2007 Nature Publishing Group REVIEWS LRRCT LRRNT WSC CLECT PKD LRR REJ LH2 mmPKD1 GPS mmPKD2 Coil dmTRPN1 ANKs TMs mmTRPA1 ceOSM-9 dm painless ceOCR-2 mmTRPV4 TRP dm nanchung mmTRPC1 scTRPY1 mmTRPML3 0 200 400 600 800 1000 aa Figure 2 | Domain structures of some TRP channels. The polycystic kidney disease (PKD1) group have much longer N-termini (connected by dashed line) than other transient receptor potential (TRP) channels. Strongly predicted transmembrane domains are represented by blue boxes and possible transmembrane domains are represented in light blue. The letters and numbers following TRP denote TRP subfamily and member, respectively. ANKs, ankyrin repeat domains; CLECT, C-type lectin domain; coil, coiled-coil domain; GPS, G-protein-coupled-receptor proteolytic-
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