TRP Channels: What Do They Look Like?

The first transient receptor potential (TRP) ion channel was identified as a locus that gave rise to a phenotype in which the photoreceptor light response decayed to baseline during prolonged illumination (Cosens and Manning, 1969; Minke et al., 1975). The identification of the TRP fly in 1969 and the molecular identification of the gene in 1975 set the stage for the subsequent explosion of discoveries that continue even today. The mid-1990s through the early 2000s were a particularly productive time for identification of many new TRP subfamilies and subfamily members. This is apparent from the rapid increase in the number of publications on TRP channels listed in PubMed (Figure 1.1); once many new TRP channels were identified, work on understanding their physiology progressed rapidly. Six subfamilies of TRP channels have now been identified in mammals, with an additional subfamily found in invertebrates and nonmammalian vertebrate animals (Figure 1.1, right panel). Because of diverse nomenclature for any given TRP channel, only the characters used to describe each column in Figure 1.1 were used as search terms. Although this approach clearly underestimates the work on all TRP channels, it likely underestimates those TRP channels with primarily clinical publications more than others. TRP channels are members of the voltage-gated superfamily of ion channels that includes the voltage gated K, Na, and Ca channels as well as related cyclic nucleotide-gated channels. They form as tetramers of identical subunits (Figure 1.2), although heterotetramers of TRP channel subunits have been reported (reviewed in Cheng et al., 2010). Like other members of the voltage-gated superfamily, each subunit includes six membrane-spanning helices with a reentrant pore loop between the fifth and six transmembrane helices, and intracellular amino- and carboxy-terminali. The first four transmembrane segments (Figure 1.2, blue) form the voltage-sensing or voltage-sensing-like domain. The remaining two transmembrane segments, along with the reentrant pore loop (Figure 1.2, yellow), form the ion-conducting pore of the channel. Although some TRP channels (e.g., TRPM8) show voltage-dependent activation (Voets et al., 2007); others show little or no voltage-dependent gating (e.g., TRPV1) (Liu et al., 2009). This variability in function is likely due to variability in the amino acid sequence in the fourth transmembrane helix, which for voltage-gated channels includes a number of positively charged residues and for voltage-independent channels does not (Figure 1.3). It is worth noting that the macroscopic current-voltage relationship of TRPV1 shows significant outward rectification. However, this is due almost exclusively to rectification in the unitary conductance (Liu et al., 2009). A hallmark of many TRP channels is the TRP domain following the sixth transmembrane helix (Figures 1.2 (purple) and 1.4). This can be recognized based on primary sequence in TRPC, TRPM, and TRPV channels. Although it was not obvious from the primary sequence of TRPA1 channels that they included a TRP domain, structural homology in this region was revealed by the recent cryoEM structures of TRPV1 (Liao et al., 2013) and TRPA1 (Paulsen et al., 2015) and is shown in Figure 1.2. The TRP domain consists of an alpha helical segment parallel and in close proximity to the plasma membrane. Although a definitive function for the TRP domain has not been established, it is positioned well to interact with both the membrane and the amino-terminal region. Three TRP subfamilies, TRPC, TRPV, and TRPA, have amino-terminal ankyrin repeat domains of varying lengths (Figures 1.2 and 1.5). TRPA1's domain is the longest, although we do not yet know how many ankyrin repeats may be present in TRPA1 channels—only that it is a large number. The function of these domains is not fully understood, but in some channels this structural element appears to influence gating. For example, in TRPV1 the ankyrin repeats contain a reactive cysteine that promotes channel opening (Salazar et al., 2008), and the region has been proposed to be a functionally important binding site for ATP (Lishko et al., 2007) and calmodulin (Rosenbaum et al., 2004). The TRP channel superfamily can be subdivided into seven separate subfamilies: TRPA, TRPC, TRPM, TRPML, TRPN, TRPP, and TRPV. The individual subunits of all seven subfamilies’ members are thought to contain six transmembrane segments that assemble as tetramers to form functional TRP channels (Figure 1.2). However, the tissue distribution, function, and even in which species each subfamily can be found vary wildly (Figure 1.6), representing the myriad roles that TRP channels play in neurobiology.