Transient receptor potential calcium channel family

TRPA1 ion channel

Structure of the TRPA1 ion channel determined by electron cryo-microscopy
Identifiers
Symbol TRP-CC
Pfam PF00520
InterPro IPR005821
SMART SM00248
PROSITE PS50088
TCDB 1.A.4
OPM superfamily 8
OPM protein 3j9p

The transient receptor potential Ca2+ channel (TRP-CC) family (TC# 1.A.4) is a member of the voltage-gated ion channel (VIC) superfamily and consists of cation channels conserved from worms to humans.[1] The TRP-CC family also consists of seven subfamilies (TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML) based on their amino acid sequence homology:

  1. the canonical or classic TRPs,
  2. the vanilloid receptor TRPs,
  3. the melastatin or long TRPs,
  4. ankyrin (whose only member is the transmembrane protein 1 [TRPA1])
  5. TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins,
  6. the polycystins
  7. and mucolipins.

A representative list of members belonging to the TRP-CC family can be found in the Transporter Classification Database.

Function

Members of the TRP-CC family are characterized as cellular sensors with polymodal activation and gating properties. Many TRP channels are activated by a variety of different stimuli and function as signal integrators.[2][3][4] These mammalian proteins have been tabulated revealing their accepted designations, activators and inhibitors, putative interacting proteins and proposed functions.[5] The founding members of the TRP superfamily are the TRPC (TRP canonical) channels, which can be activated following the stimulation of phospholipase C and/or depletion of internal calcium stores.[3] However, the precise mechanisms leading to TRPC activation remain unclear. TRPC channels regulate nicotine-dependent behavior.[6]

One member of the TRP-CC family, TRP-PLIK (1862 aas; AF346629), has been implicated in the regulation of cell division. It has an N-terminal TRP-CC-like sequence and a C-terminal protein kinase-like sequence. It was shown to autophosphorylate and exhibits an ATP phosphorylation-dependent, non-selective, Ca2+-permeable, outward rectifying conductance.[7] Another long homologue, Melastatin, is associated with melanocytic tumor progression whereas another homologue, MTR1, is associated with Beckwith-Wiedemann syndrome and a predisposition for neoplasia. Each of these proteins may be present in the cell as several splice variants.

The ability to detect variations in humidity is critical for many animals. Birds, reptiles and insects all show preferences for specific humidities that influence their mating, reproduction and geographic distribution. Because of their large surface area to volume ratio, insects are particularly sensitive to humidity, and its detection can influence their survival. Two types of hygroreceptors exist in insects: one responds to an increase (moist receptor) and the other to a reduction (dry receptor) in humidity. Although previous data indicated that mechanosensation might contribute to hygrosensation, the cellular basis of hygrosensation and the genes involved in detecting humidity remain unknown. To understand better the molecular bases of humidity sensing, investigated several genes encoding channels associated with mechanosensation, thermosensing or water transport.[8]

Transport reaction

The generalized transport reaction catalyzed by TRP-CC family members is:

Ca2+ (out) ⇌ Ca2+ (in)

or

C+ and Ca2+ (out) ⇌ C+ and Ca2+ (in).

Anesthesia

Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. These anaesthetics block sodium channels and the excitability of neurons. Binshtok et al. (2007) tested the possibility that the excitability of primary sensory nociceptor (pain-sensing) neurons could be blocked by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel (TC #1.A.4.2.1).[9] They found that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability.[9]

Structure

Members of the VIC (TC# 1.A.1), RIR-CaC (TC# 2.A.3) and TRP-CC (TC# 1.A.4) families have similar transmembrane domain structures, but very different cytosolic domain structures.[10]

The proteins of the TRP-CC family exhibit the same topological organization with a probable KscA-type 3-dimensional structure.[11][12] They consist of about 700-800 (VR1, SIC or ECaC) or 1300 (TRP proteins) amino acyl residues (aas) with six transmembrane spanners (TMSs) as well as a short hydrophobic 'loop' region between TMSs 5 and 6. This loop region may dip into the membrane and contribute to the ion permeation pathway.[13]

All members of the vanilloid family of TRP channels (TRPV) possess an N-terminal ankyrin repeat domain (ARD), which regulates calcium uptake and homeostasis. It is essential for channel assembly and regulation. The 1.7 Å crystal structure of the TRPV6-ARD revealed conserved structural elements unique to the ARDs of TRPV proteins. First, a large twist between the fourth and fifth repeats is induced by residues conserved in all TRPV ARDs. Second, the third finger loop is the most variable region in sequence, length and conformation. In TRPV6, a number of putative regulatory phosphorylation sites map to the base of this third finger. The TRPV6-ARD does not assemble as a tetramer and is monomeric in solution.[14] Voltage sensing in thermo-TRP channels has been reviewed by Brauchi et al.[15]

TRP channels are calcium-permeable nonselective cation channels with six TMS domains and a putative pore loop between TMSs 5 and 6.[16] About 28 mammalian TRP channels have been identified, with different numbers of splicing variants for each channel gene. TRP channels have been classified into six different subgroups, including TRPV (1-6), TRPM (1-8), TRPC (1-7), TRPA1, TRPP (1-3), and TRPML (1-3), according to their sequence similarities. In general, TRP channels are involved in calcium handling (e.g., intracellular calcium mobilization and calcium reabsorption) and a broad range of sensory modalities, including pain, temperature, taste, etc. TRP channelopathies are part of important mechanisms in a variety of diseases such as neurodegenerative disorders, diabetes mellitus, inflammatory bowel diseases, epilepsy, cancer, etc. Several members of the TRP family, TRPV1-4, TRPM8, and TRPA1, also called 'ThermoTRPs,' are involved in the detection of temperature changes, thus acting as the molecular thermometers of our body. They are also polymodal nociceptors that integrate painful stimuli such as noxious temperatures and chemical insults. For example, the TRPV1 channel mediates thermal hyperalgesia and pain induced by capsaicin and acid. TRPA1 is a nociceptor that integrates many noxious environmental stimuli including oxidants and electrophilic agents. Gene deletion animals have been created to study the role of TRP channels in pain and nociception; involvement of TRPV1, TRPV3, TRPV4, and TRPA1 in nociception has been confirmed.[16]

Crystal structures

There are several crystal structures available for members of the TRP-CC family. Some of these include:

VR1: PDB: 2NYJ​, 2NYN​, 3J5P​, 3J5Q​, 3J5R​

TRPV2 aka VRL-1: PDB: 2F37​

Transient receptor potential cation channel subfamily A member 1: PDB: 3J9P​

See also

References

  1. ↑ Vennekens, Rudi; Menigoz, Aurelie; Nilius, Bernd (2012-01-01). "TRPs in the Brain". Reviews of Physiology, Biochemistry and Pharmacology 163: 27–64. doi:10.1007/112_2012_8. ISSN 0303-4240. PMID 23184016.
  2. ↑ Latorre, Ramon; Zaelzer, Cristián; Brauchi, Sebastian (2009-08-01). "Structure-functional intimacies of transient receptor potential channels". Quarterly Reviews of Biophysics 42 (3): 201–246. doi:10.1017/S0033583509990072. ISSN 1469-8994. PMID 20025796.
  3. 1 2 Montell, Craig (2005-02-22). "The TRP superfamily of cation channels". Science's STKE: signal transduction knowledge environment 2005 (272): re3. doi:10.1126/stke.2722005re3. ISSN 1525-8882. PMID 15728426.
  4. ↑ Ramsey, I. Scott; Delling, Markus; Clapham, David E. (2006-01-01). "An introduction to TRP channels". Annual Review of Physiology 68: 619–647. doi:10.1146/annurev.physiol.68.040204.100431. ISSN 0066-4278. PMID 16460286.
  5. ↑ Clapham, David E. (2007-04-06). "SnapShot: mammalian TRP channels". Cell 129 (1): 220. doi:10.1016/j.cell.2007.03.034. ISSN 0092-8674. PMID 17418797.
  6. ↑ Feng, Zhaoyang; Li, Wei; Ward, Alex; Piggott, Beverly J.; Larkspur, Erin R.; Sternberg, Paul W.; Xu, X. Z. Shawn (2006-11-03). "A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels". Cell 127 (3): 621–633. doi:10.1016/j.cell.2006.09.035. ISSN 0092-8674. PMC 2859215. PMID 17081982.
  7. ↑ Runnels, L. W.; Yue, L.; Clapham, D. E. (2001-02-09). "TRP-PLIK, a bifunctional protein with kinase and ion channel activities". Science (New York, N.Y.) 291 (5506): 1043–1047. doi:10.1126/science.1058519. ISSN 0036-8075. PMID 11161216.
  8. ↑ Liu, Lei; Li, Yuhong; Wang, Runping; Yin, Chong; Dong, Qian; Hing, Huey; Kim, Changsoo; Welsh, Michael J. (2007-11-08). "Drosophila hygrosensation requires the TRP channels water witch and nanchung". Nature 450 (7167): 294–298. doi:10.1038/nature06223. ISSN 1476-4687. PMID 17994098.
  9. 1 2 Binshtok, Alexander M.; Bean, Bruce P.; Woolf, Clifford J. (2007-10-04). "Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers". Nature 449 (7162): 607–610. doi:10.1038/nature06191. ISSN 1476-4687. PMID 17914397.
  10. ↑ Mio, Kazuhiro; Ogura, Toshihiko; Sato, Chikara (2008-05-01). "Structure of six-transmembrane cation channels revealed by single-particle analysis from electron microscopic images". Journal of Synchrotron Radiation 15 (Pt 3): 211–214. doi:10.1107/S0909049508004640. ISSN 0909-0495. PMC 2394823. PMID 18421141.
  11. ↑ Dodier, Yolaine; Banderali, Umberto; Klein, Hélène; Topalak, Ozlem; Dafi, Omar; Simoes, Manuel; Bernatchez, Gérald; Sauvé, Rémy; Parent, Lucie (2004-02-20). "Outer pore topology of the ECaC-TRPV5 channel by cysteine scan mutagenesis". The Journal of Biological Chemistry 279 (8): 6853–6862. doi:10.1074/jbc.M310534200. ISSN 0021-9258. PMID 14630907.
  12. ↑ Dohke, Yoko; Oh, Young S.; Ambudkar, Indu S.; Turner, R. James (2004-03-26). "Biogenesis and topology of the transient receptor potential Ca2+ channel TRPC1". The Journal of Biological Chemistry 279 (13): 12242–12248. doi:10.1074/jbc.M312456200. ISSN 0021-9258. PMID 14707123.
  13. ↑ Hardie, R. C.; Minke, B. (1993-09-01). "Novel Ca2+ channels underlying transduction in Drosophila photoreceptors: implications for phosphoinositide-mediated Ca2+ mobilization". Trends in Neurosciences 16 (9): 371–376. ISSN 0166-2236. PMID 7694408.
  14. ↑ Phelps, Christopher B.; Huang, Robert J.; Lishko, Polina V.; Wang, Ruiqi R.; Gaudet, Rachelle (2008-02-26). "Structural analyses of the ankyrin repeat domain of TRPV6 and related TRPV ion channels". Biochemistry 47 (8): 2476–2484. doi:10.1021/bi702109w. ISSN 0006-2960. PMC 3006163. PMID 18232717.
  15. ↑ Brauchi, Sebastian; Orio, Patricio (2011-01-01). "Voltage sensing in thermo-TRP channels". Advances in Experimental Medicine and Biology 704: 517–530. doi:10.1007/978-94-007-0265-3_28. ISSN 0065-2598. PMID 21290314.
  16. 1 2 Hu, Hongzhen; Bandell, Michael; Grandl, Jorg; Petrus, Matt (2011-01-01). Zhu, Michael X., ed. High-Throughput Approaches to Studying Mechanisms of TRP Channel Activation. Boca Raton (FL): CRC Press/Taylor & Francis. ISBN 9781439818602. PMID 22593966.

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