1.1. Introduction

The first transient receptor potential (TRP) ion channel was identified as a Drosophila 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 trp 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.

Figure 1.1

Search terms used were (TRP OR [transient receptor potential] AND channel). Numbers were corrected by subtracting 20 publications/year—our estimate of off-target publications identified by these search terms.

TRP channels are members of the voltage-gated superfamily of ion channels that includes the voltage gated K⁺, Na⁺, and Ca²⁺ 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.

Figure 1.2

Structural arrangement of TRP channels whose structures have recently been elucidated. In the top row are structures of the indicated TRP channels, with one subunit shown in color. Below is a zoomed-in view of one subunit from TRPV1 to highlight the structure (more...)

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).

Figure 1.3

Sequence alignment of S4 membrane-spanning helices, with positive “gating charge” residues indicated in red. Histidine is colored pink to indicate its ability to be protonated and thus carry charge at near-physiological pH. The alignment (more...)

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.

Figure 1.4

Sequence alignment of the region following the S6 transmembrane helix and including the TRP domain or TRP box. TRP channel family members are indicated to the left. The character “r” preceding each protein name indicates all sequences (more...)

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).

Figure 1.5

A cartoon representation of various functional domains found in TRP channels. In all TRP channels, single subunits contain six transmembrane segments, S1–S6 (top). S1–S4 form a voltage sensor-like domain (left), whereas S5 and S6 form (more...)

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.

Figure 1.6

Expression profiles of TRP channels in humans. Colored boxes under each TRP channel name correspond to the colors of various organs on the left, indicating in which tissues each channel has been identified. Evidence for expression at the RNA level is (more...)

1.2. TRPA

The TRPA subfamily contains only one member, TRPA1, so named for its extensive N-terminal ankyrin repeat domain (ARD) (Figure 1.2). Whereas many TRP channels contain an ARD, with at least 14 ankyrin repeats TRPA1 has the most of any identified mammalian TRP. The gene encoding TRPA1 is conserved from flies to mammals, and in humans the protein is expressed in sensory nerves, as well as other tissues. TRPA1's activity can be regulated by temperature, as with members of the TRPV and TRPM family; however, TRPA1's temperature sensitivity is strongly species dependent, with different species demonstrating wildly different temperature activation profiles for TRPA1 (reviewed in Laursen et al., 2015).

1.3. TRPC

The TRPC (for “classical” or “canonical”) subfamily contains the TRP channels most closely related to the first identified TRP channel (Cosens and Manning, 1969; Minke et al., 1975). Since the discovery and cloning of the original trp locus in Drosophila, seven TRPC genes have been reported. Humans contain genes encoding TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7, but lack the TRPC2 gene found in mice and other species.

1.4. TRPM

In many ways, the TRPM subfamily is the most enigmatic and diverse of the TRPs. Its founding member, TRPM1, derives its name (“TRP melastatin 1”) from its putative role as a melanoma suppressor (Duncan et al., 1998). Whereas currents sensitive to TRPM1 siRNA have been recorded from melanocytes, attempts to record activity directly from recombinant TRPM1 have been so far unsuccessful (Oancea et al., 2009). This subfamily also contains the unique class of “chanzymes,” in which an enzymatic domain has been evolutionarily fused to the TRP channel (Figure 1.5). Such chanzymes include TRPM2, which contains a NUDT9 homology domain that hydrolyzes adenosine diphosphate ribose (Kuhn and Luckhoff, 2004), and TRPM6 and TRPM7, and each contain a functional protein kinase (Runnels et al., 2001). TRPM8 is perhaps the best-studied member of the TRPMs, and is activated by noxious cold, and chemical compounds such as menthol and eucalyptus (McKemy et al., 2002). Recent work has also demonstrated that TRPM8 can serve as a physiologically relevant receptor for testosterone (Asuthkar et al., 2015a; Asuthkar et al., 2015b).

1.5. TRPML

The three mucolipins, TRPML1–3 (also known as MCOLN1–3) are named after loss of function mutations in TRPML1 that result in the neurodegenerative disease type IV mucolipidosis (reviewed in Slaugenhaupt, 2002). TRPMLs are the most distantly connected subfamily and lack the extensive cytoplasmic N- and C-termini found in many other TRPs. This may be related to their subcellular localization; whereas many TRPs are known to traffic to the plasma membrane where they exert their physiological functions, TRPMLs predominantly localize to intracellular membranes of the endo- and exocytosis pathways (reviewed in Venkatachalam et al., 2015). Although the endogenous regulation of TRPMLs is not well understood, it is known that the activity of these channels is regulated by phosphoinositides (Dong et al., 2010), as is true for most other TRP channels (Zheng and Trudeau, 2015). Recently, synthetic agonists for the TRPMLs have been developed to facilitate further study of these channels (Shen et al., 2012; Grimm et al., 2010).

1.6. TRPN

Absent from mammals, the TRPN (“No mechanoreceptor potential C,” also called NOMPC) protein forms a mechanosensitive channel (Walker et al., 2000). Mechanosensitivity is imparted by the N-terminal ARD, which dwarfs even TRPA1's, with its 29 ankyrin repeats. These ankyrin repeats have been shown to interact with cellular microtubules, and this association is required to impart mechanosensitivity to the channels (Zhang et al., 2015).

1.7. TRPP

The TRPPs, or polycystins, are similar to the TRPMLs in that they were identified from disease-causing mutations, and bear little similarity to the rest of the TRP superfamily (Mochizuki et al., 1996). Although TRPPs are among the most widely expressed TRPs (Figure 1.6), the effects of human mutations in TRPP1 are relatively limited to the kidney, where such mutations cause autosomal dominant polycystic kidney disease (ADPKD) (reviewed in Ong and Harris, 2015). TRPP1 interacts with PKD1, an 11 transmembrane domain protein also mutated in ADPKD (Hanaoka et al., 2000). This association was originally suggested to be required for TRPP1 to form functional channels (Hanaoka et al., 2000); however, recent studies have questioned this interpretation (DeCaen et al., 2016; Shen et al., 2016). Two other TRPPs—TRPP2 and TRPP3 (also called PKD2L2 and TRPP5)—have been identified, and TRPP2 has been suggested to be the receptor for sour tastes (Huang et al., 2006; Ishimaru et al., 2006; LopezJimenez et al., 2006). TRPPs are often found localized to primary cilia, where it has been proposed that they have a role in regulating flow-induced calcium transients (Nauli et al., 2003), although recent pressure-clamp studies of primary cilia indicate that TRPPs in primary cilia are only mechanosensitive at high pressures (DeCaen et al., 2013).

The nomenclature of TRPPs can often be confusing, because of the original inclusion of the PKD1 family in the TRPPs. For this reason, TRPP1 was originally designated TRPP2, and so on. However, because the PKD1 family proteins contain 11 transmembrane domains and have not been found to form conductive channels, it has been suggested that a consistent nomenclature should leave the PKDs out of the TRPP family. For completeness, we list here the gene name for each TRPP (in italics), followed by possible aliases that are still prevalent in the literature: TRPP1 (PKD2, PKD2, TRPP2, polycystin-2); TRPP2 (PKD2L1, PKD2L1, TRPP3, polycystin-L); TRPP3 (PKD2L2, PKD2L2, TRPP5).

1.8. TRPV

TRPVs are named for the role of the founding member, TRPV1, as the receptor for the pungent vanilloid capsaicin (Caterina et al., 1997). Despite this nomenclature, only TRPV1 has so far been shown to be gated by vanilloids. TRPVs are by far the best-studied TRP subfamily (Figure 1.1), in large part due to the pharmacological accessibility and clear knockout phenotype of TRPV1 (Caterina et al., 1997). TRPV1 is highly expressed in sensory nerves (Figure 1.6), where it acts as a multimodal integrator of noxious stimuli, gating in response to noxious compounds, heat, lipids, and protons (Caterina et al., 1997, 2000; Lukacs et al., 2007, 2013; Rohacs et al., 2008; Klein et al., 2008; Senning et al., 2014; Ufret-Vincenty et al., 2015). TRPV1 was the first TRP for which a near-atomic structural model was determined (Liao, 2013), confirming that TRPs form tetramers of subunits with six transmembrane domains each (Figure 1.2). The TRPV family also includes the mechanosensitive channels TRPV4 and TRPY1 (the yeast homologue to TRPV channels) (Palmer et al., 2001; Strotmann et al., 2000; Liedtke et al., 2000). Alternative splice variants of TRPV1 are also thought to be mechanosensitive, responding to changes in osmotic pressure (Sharif Naeini et al., 2006; Zaelzer et al., 2015). Most TRPV channels display calcium-dependent modulation in addition to being permeable to calcium (reviewed in Gordon-Shaag et al., 2008), and TRPV5 and TRPV6 have been shown to be directly modulated by CaM (Lambers et al., 2004).

1.9. Conclusion

The number of TRP channel structures that have been solved has grown rapidly since the first TRPV1 structure was solved only a few short years ago (Liao et al., 2013; Paulsen et al., 2015; Huynh et al., 2016; Zubcevic et al., 2016; Saotome et al., 2016). Most recently, the first structure of a TRPP family member (PKD2, or TRPP1) was solved (Shen et al., 2016), highlighting key structural differences between these proteins and the more closely related TRPV and TRPA structures (Figure 1.2). Although these structures have provided unprecedented insight into the elegant molecular machinery that underlies TRP channel function, they also indicate that there is much work left to do. Future studies to probe the precise conformational rearrangements that occur to produce channel gating will be required to fully understand these channels’ roles in normal physiology, and to guide the design of TRP-targeted therapeutics. Furthermore, the number of TRP structures determined so far represents only a fraction of the TRP superfamily, leaving open the possibility of future structural surprises in the TRP world.

References

• Asuthkar, S. et al. 2015a. The TRPM8 protein is a testosterone receptor: II. Functional evidence for an ionotropic effect of testosterone on TRPM8. J Biol Chem, 290(5): 2670–2688. [PMC free article: PMC4316998] [PubMed: 25480785]
• Asuthkar, S. et al. 2015b. The TRPM8 protein is a testosterone receptor: I. Biochemical evidence for direct TRPM8-testosterone interactions. J Biol Chem, 290(5): 2659–2669. [PMC free article: PMC4317017] [PubMed: 25480783]
• Caterina, M.J. et al. 1997. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature, 389(6653): 816–824. [PubMed: 9349813]
• Caterina, M.J. et al. 2000. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 288(5464): 306–313. [PubMed: 10764638]
• Cheng, W., C. Sun, and J. Zheng. 2010. Heteromerization of TRP channel subunits: Extending functional diversity. Protein Cell, 1(9): 802–810. [PMC free article: PMC4875230] [PubMed: 21203922]
• Cosens, D.J. and A. Manning. 1969. Abnormal electroretinogram from a Drosophila mutant. Nature, 224(5216): 285–287. [PubMed: 5344615]
• DeCaen, P.G. et al. 2013. Direct recording and molecular identification of the calcium channel of primary cilia. Nature, 504(7479): 315–318. [PMC free article: PMC4073646] [PubMed: 24336289]
• DeCaen, P.G. et al. 2016. Atypical calcium regulation of the PKD2-L1 polycystin ion channel. Elife, 5. [PMC free article: PMC4922860] [PubMed: 27348301]
• Dong, X.P. et al. 2010. PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca(2+) release channels in the endolysosome. Nat Commun, 1: 38. [PMC free article: PMC2928581] [PubMed: 20802798]
• Duncan, L.M. et al. 1998. Down-regulation of the novel gene melastatin correlates with potential for melanoma metastasis. Cancer Res, 58(7): 1515–1520. [PubMed: 9537257]
• Gordon-Shaag, A., W.N. Zagotta, and S.E. Gordon. 2008. Mechanism of Ca(2+)-dependent desensitization in TRP channels. Channels (Austin), 2(2): 125–129. [PubMed: 18849652]
• Grimm, C. et al. 2010. Small molecule activators of TRPML3. Chem Biol, 17(2): 135–148. [PMC free article: PMC2834294] [PubMed: 20189104]
• Hanaoka, K. et al. 2000. Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature, 408(6815): 990–994. [PubMed: 11140688]
• Huang, A.L. et al. 2006. The cells and logic for mammalian sour taste detection. Nature, 442(7105): 934–938. [PMC free article: PMC1571047] [PubMed: 16929298]
• Huynh, K.W. et al. 2016. Structure of the full-length TRPV2 channel by cryo-EM. Nat Commun, 7: 11130. [PMC free article: PMC4820614] [PubMed: 27021073]
• Ishimaru, Y. et al. 2006. Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proc Natl Acad Sci U S A, 103(33): 12569–12574. [PMC free article: PMC1531643] [PubMed: 16891422]
• Klein, R.M. et al. 2008. Determinants of molecular specificity in phosphoinositide regulation. Phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) is the endogenous lipid regulating TRPV1. J Biol Chem, 283(38): 26208–26216. [PMC free article: PMC2533779] [PubMed: 18574245]
• Kuhn, F.J. and A. Luckhoff. 2004. Sites of the NUDT9-H domain critical for ADP-ribose activation of the cation channel TRPM2. J Biol Chem, 279(45): 46431–46437. [PubMed: 15347676]
• Lambers, T.T. et al. 2004. Regulation of the mouse epithelial Ca2(+) channel TRPV6 by the Ca(2+)-sensor calmodulin. J Biol Chem, 279(28): 28855–28861. [PubMed: 15123711]
• Laursen, W.J. et al. 2015. Species-specific temperature sensitivity of TRPA1. Temperature (Austin), 2(2): 214–226. [PMC free article: PMC4843866] [PubMed: 27227025]
• Liao, M. et al. 2013. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature, 504(7478): 107–112. [PMC free article: PMC4078027] [PubMed: 24305160]
• Liedtke, W. et al. 2000. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell, 103(3): 525–535. [PMC free article: PMC2211528] [PubMed: 11081638]
• Lishko, P.V. et al. 2007. The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity. Neuron, 54(6): 905–918. [PubMed: 17582331]
• Liu, B. et al. 2009 Proton inhibition of unitary currents of vanilloid receptors. J Gen Physiol, 134(3): 243–258. [PMC free article: PMC2737227] [PubMed: 19720962]
• LopezJimenez, N.D. et al. 2006. Two members of the TRPP family of ion channels, Pkd1l3 and Pkd2l1, are co-expressed in a subset of taste receptor cells. J Neurochem, 98(1): 68–77. [PubMed: 16805797]
• Lukacs, V. et al. 2007. Dual regulation of TRPV1 by phosphoinositides. J Neurosci, 27(26): 7070–7080. [PMC free article: PMC6672228] [PubMed: 17596456]
• Lukacs, V. et al. 2013. Distinctive changes in plasma membrane phosphoinositides underlie differential regulation of TRPV1 in nociceptive neurons. J Neurosci, 33(28): 11451–11463. [PMC free article: PMC3724548] [PubMed: 23843517]
• McKemy, D.D., W.M. Neuhausser, and D. Julius. 2002. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature, 416(6876): 52–58. [PubMed: 11882888]
• Minke, B., C. Wu, and W.L. Pak. 1975. Induction of photoreceptor voltage noise in the dark in Drosophila mutant. Nature, 258(5530): 84–87. [PubMed: 810728]
• Mochizuki, T. et al. 1996. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science, 272(5266): 1339–1342. [PubMed: 8650545]
• Nauli, S.M. et al. 2003. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet, 33(2): 129–137. [PubMed: 12514735]
• Oancea, E. et al. 2009. TRPM1 forms ion channels associated with melanin content in melanocytes. Sci Signal, 2(70): ra21. [PMC free article: PMC4086358] [PubMed: 19436059]
• Ong, A.C. and P.C. Harris. 2015. A polycystin-centric view of cyst formation and disease: The polycystins revisited. Kidney Int, 88(4): 699–710. [PMC free article: PMC4589452] [PubMed: 26200945]
• Palmer, C.P. et al. 2001. A TRP homolog in Saccharomyces cerevisiae forms an intracellular Ca(2+)-permeable channel in the yeast vacuolar membrane. Proc Natl Acad Sci U S A, 98(14): 7801–7805. [PMC free article: PMC35422] [PubMed: 11427713]
• Paulsen, C.E. et al. 2015. Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature, 525(7570): 552. [PubMed: 26200340]
• Rohacs, T., B. Thyagarajan, and V. Lukacs. 2008. Phospholipase C mediated modulation of TRPV1 channels. Mol Neurobiol, 37(2–3): 153–163. [PMC free article: PMC2568872] [PubMed: 18528787]
• Rosenbaum, T. et al. 2004. Ca2+/calmodulin modulates TRPV1 activation by capsaicin. J Gen Physiol, 123(1): 53–62. [PMC free article: PMC2217413] [PubMed: 14699077]
• Runnels, L.W., L. Yue, and D.E. Clapham. 2001. TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science, 291(5506): 1043–1047. [PubMed: 11161216]
• Salazar, H. et al. 2008. A single N-terminal cysteine in TRPV1 determines activation by pungent compounds from onion and garlic. Nat Neurosci, 11(3): 255–261. [PMC free article: PMC4370189] [PubMed: 18297068]
• Saotome, K. et al. 2016. Crystal structure of the epithelial calcium channel TRPV6. Nature, 534(7608): 506–511. [PMC free article: PMC4919205] [PubMed: 27296226]
• Senning, E.N. et al. 2014. Regulation of TRPV1 ion channel by phosphoinositide (4,5)-bisphosphate: The role of membrane asymmetry. J Biol Chem, 289(16): 10999–11006. [PMC free article: PMC4036241] [PubMed: 24599956]
• Sharif Naeini, R. et al. 2006. An N-terminal variant of Trpv1 channel is required for osmosensory transduction. Nat Neurosci, 9(1): 93–98. [PubMed: 16327782]
• Shen, D. et al. 2012. Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat Commun, 3: 731. [PMC free article: PMC3347486] [PubMed: 22415822]
• Shen, P.S. et al. 2016. The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Cell, 167(3): 763–773 e11. [PMC free article: PMC6055481] [PubMed: 27768895]
• Slaugenhaupt, S.A. 2002. The molecular basis of mucolipidosis type IV. Curr Mol Med, 2(5): 445–450. [PubMed: 12125810]
• Strotmann, R. et al. 2000. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol, 2(10): 695–702. [PubMed: 11025659]
• Ufret-Vincenty, C.A. et al. 2015. Mechanism for phosphoinositide selectivity and activation of TRPV1 ion channels. J Gen Physiol, 145(5): 431–442. [PMC free article: PMC4411251] [PubMed: 25918361]
• Venkatachalam, K., C.O. Wong, and M.X. Zhu. 2015. The role of TRPMLs in endolysosomal trafficking and function. Cell Calcium, 58(1): 48–56. [PMC free article: PMC4412768] [PubMed: 25465891]
• Voets, T. et al. 2007. TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli. Nat Chem Biol, 3(3): 174–182. [PubMed: 17293875]
• Walker, R.G., A.T. Willingham, and C.S. Zuker. 2000. A Drosophila mechanosensory transduction channel. Science, 287(5461): 2229–2234. [PubMed: 10744543]
• Zaelzer, C. et al. 2015. DeltaN-TRPV1: A molecular co-detector of body temperature and osmotic stress. Cell Rep, 13(1): 23–30. [PubMed: 26387947]
• Zhang, W. et al. 2015. Ankyrin repeats convey force to gate the NOMPC mechanotransduction channel. Cell, 162(6): 1391–1403. [PMC free article: PMC4568062] [PubMed: 26359990]
• Zheng, J. and M. Trudeau. 2015. Handbook of Ion Channels. Boca Raton, FL: CRC Press.
• Zubcevic, L. et al. 2016. Cryo-electron microscopy structure of the TRPV2 ion channel. Nat Struct Mol Biol, 23(2): 180–186. [PMC free article: PMC4876856] [PubMed: 26779611]