TRPM8 | Transient Receptor Potential channels | IUPHAR/BPS Guide to PHARMACOLOGY

TRPM8

Target id: 500

Nomenclature: TRPM8

Family: Transient Receptor Potential channels

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   GtoImmuPdb view: OFF :     Currently no data for TRPM8 in GtoImmuPdb

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 1104 2q37.1 TRPM8 transient receptor potential cation channel subfamily M member 8 23
Mouse 6 1 1104 1 D Trpm8 transient receptor potential cation channel, subfamily M, member 8 18
Rat 6 1 1104 9q35 Trpm8 transient receptor potential cation channel, subfamily M, member 8 15
Previous and Unofficial Names
LTrpC6 | CMR1 | cold/menthol receptor 1 | transient receptor potential cation channel
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the cold- and menthol-sensing ion channel TRPM8
PDB Id:  6BPQ
Resolution:  4.1Å
Species:  Human
References:  26
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Gq-alpha 28
Functional Characteristics
γ = 40-83 pS at positive potentials; conducts mono- and di-valent cations non-selectively (PCa/PNa = 1.0–3.3); pronounced outward rectification; demonstrates densensitization to chemical agonists and adaptation to a cold stimulus in the presence of Ca2+; modulated by lysophospholipids and PUFAs
Ion Selectivity and Conductance
Species:  Mouse
Rank order:  Cs+ > K+ > Na+
References:  18
Species:  Rat
Rank order:  Ca2+ [83.0 pS] > K+ = Na+ = Cs+ [42.0 pS]
References:  10,15,27
Ion Selectivity and Conductance Comments
Single channel conductance (rat) = 83 pS [15]
PCa:PNa ratio = 0.97-3.3 [15,18]
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -10.0 – 80.0 - 5 HEK 293 cells transiently transfected with rTrpm8. Rat
Inactivation  - -
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  25.0 – 200.0 1.0 – 15.0 25 HEK 293 cells transiently transfected with TRPM8. Human
Inactivation  - -
Comments  TRPM8 is weakly voltage dependent.
Chemical activators (Human)
agonist activities are temperature dependent and potentiated by cooling
Physical activators (Human)
depolarization (V½ ~ +50 mV at 15°C), cooling (< 22-26°C)

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
icilin Mm Agonist 6.7 – 6.9 pEC50 - Physiological 2,4
pEC50 6.7 – 6.9 (EC50 1.99x10-7 – 1.25x10-7 M) [2,4]
Holding voltage: Physiological
icilin Rn Full agonist 6.4 pEC50 - Physiological 15-16,18
pEC50 6.4 Icilin activation is Ca2+-dependent. [15-16,18]
Holding voltage: Physiological
Description: Whole-cell voltage-clamp recordings or Ca2+-microfluorimetry in heterologous cells (HEK, CHO, and Xenopus oocytes) expressing TRPM8.
frescolat ML Mm Partial agonist 5.5 pEC50 - Physiological 4
pEC50 5.5 [4]
Holding voltage: Physiological
WS-3 Mm Partial agonist 5.4 pEC50 - Physiological 4
pEC50 5.4 [4]
Holding voltage: Physiological
frescolat MGA Mm Partial agonist 5.3 pEC50 - Physiological 4
pEC50 5.3 [4]
Holding voltage: Physiological
cooling agent 10 Mm Partial agonist 5.2 pEC50 - Physiological 4
pEC50 5.2 [4]
Holding voltage: Physiological
WS-12 Rn Full agonist 4.9 pEC50 - Physiological 13,20
pEC50 4.9 (EC50 1.25x10-5 M) [13,20]
Holding voltage: Physiological
Description: Whole-cell voltage-clamp recordings or Ca2+-microfluorimetry in heterologous cells (HEK, CHO, and Xenopus oocytes) expressing TRPM8
(+)-menthol Mm Partial agonist 4.8 pEC50 - Physiological 4
pEC50 4.8 [4]
Holding voltage: Physiological
(-)-menthol Mm Partial agonist 4.0 – 5.4 pEC50 - Physiological 2,4
pEC50 4.0 – 5.4 [2,4]
Holding voltage: Physiological
(-)-menthol Hs - 4.6 pEC50 - -120.0 – 160.0 25
pEC50 4.6 (EC50 2.51x10-5 M) inhibited by intracellular Ca2+ [25]
Holding voltage: -120.0 – 160.0 mV
WS-5 Rn Full agonist 4.6 pEC50 - Physiological 20
pEC50 4.6 [20]
Holding voltage: Physiological
Description: Whole-cell voltage-clamp recordings or Ca2+-microfluorimetry in heterologous cells (HEK, CHO, and Xenopus oocytes) expressing TRPM8
PMD38 Mm Partial agonist 4.5 pEC50 - Physiological 4
pEC50 4.5 [4]
Holding voltage: Physiological
CPS125 Rn Full agonist 4.5 pEC50 - Physiological 20
pEC50 4.5 [20]
Holding voltage: Physiological
Description: Whole-cell voltage-clamp recordings or Ca2+<.sup>-microfluorimetry in heterologous cells (HEK, CHO, and Xenopus oocytes) expressing TRPM8
WS-23 Mm Partial agonist 4.4 pEC50 - Physiological 4
pEC50 4.4 [4]
Holding voltage: Physiological
isopulegol Mm Partial agonist 4.2 pEC50 - Physiological 4
pEC50 4.2 [4]
Holding voltage: Physiological
(-)-menthol Rn Partial agonist 4.1 – 4.2 pEC50 - -60.0 15
pEC50 4.1 – 4.2 [15]
Holding voltage: -60.0 mV
frescolat ML Rn Full agonist 3.8 pEC50 - Physiological 4,20
pEC50 3.8 [4,20]
Holding voltage: Physiological
Description: Whole-cell voltage-clamp recordings or Ca2+-microfluorimetry in heterologous cells (HEK, CHO, and Xenopus oocytes) expressing TRPM8
eucalyptol Rn Partial agonist 2.5 pEC50 - -60.0 15
pEC50 2.5 [15]
Holding voltage: -60.0 mV
geraniol Mm Partial agonist 2.2 pEC50 - Physiological 4
pEC50 2.2 [4]
Holding voltage: Physiological
linalool Mm Partial agonist 2.2 pEC50 - Physiological 4
pEC50 2.2 [4]
Holding voltage: Physiological
eucalyptol Mm Partial agonist 2.1 pEC50 - Physiological 4
pEC50 2.1 [4]
Holding voltage: Physiological
hydroxycitronellal Mm Partial agonist 1.7 pEC50 - Physiological 4
pEC50 1.7 [4]
Holding voltage: Physiological
View species-specific activator tables
Activator Comments
Cold temperatures below 26°C activate TRPM8 and agonists shift the temperature sensitivity of the channel towards warmer temperatures [15]. Channel activation requires the presence of the phospholipid PIP2 in the membrane [19]. Icilin requires Ca2+ as a co-factor for full agonist activity.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
example 104 [WO2012124825] Hs Antagonist 9.1 pIC50 24
pIC50 9.1 (IC50 9x10-10 M) [24]
Description: Inhibition of menthol-induced intracellular calcium mobilisation using HEK293 cells stably expressing hTRPM8.
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
PBMC Rn Inhibition 9.3 pIC50 - Physiological 11
pIC50 9.3 (IC50 5x10-10 M) [11]
Holding voltage: Physiological
Description: Whole-cell voltage-clamp recordings or Ca2+-microfluorimetry in heterologous cells (HEK) expressing TRPM8
M8-B Rn Pore blocker 7.2 – 8.1 pIC50 - Physiological 1
pIC50 7.2 – 8.1 (IC50 6.43x10-8 – 7.8x10-9 M) Inhibited activation by cold (IC50 = 7.8nM); icilin (IC50 = 26.9nM), or menthol (IC50 = 64.3nM) in a concentration-dependent manner. [1]
Holding voltage: Physiological
BCTC Mm Antagonist 6.1 pIC50 - Physiological 4
pIC50 6.1 (IC50 8x10-7 M) [4]
Holding voltage: Physiological
Description: Whole-cell voltage-clamp recordings or Ca2+-microfluorimetry in heterologous cells (HEK, CHO, and Xenopus oocytes) expressing TRPM8
thio-BCTC Mm Antagonist 5.5 pIC50 - Physiological 4
pIC50 5.5 [4]
Holding voltage: Physiological
thio-BCTC Rn Inhibition 5.5 pIC50 - Physiological 4,14
pIC50 5.5 [4,14]
Holding voltage: Physiological
Description: Whole-cell voltage-clamp recordings or Ca2+-microfluorimetry in heterologous cells (HEK) expressing TRPM8
2-APB Mm Antagonist 4.9 – 5.1 pIC50 - 100.0 – -100.0 9,17
pIC50 4.9 – 5.1 [9,17]
Holding voltage: 100.0 – -100.0 mV
capsazepine Mm Antagonist 4.7 pIC50 - Physiological 4
pIC50 4.7 (IC50 1.8x10-5 M) [4]
Holding voltage: Physiological
5-benzyloxytryptamine Hs - - - - -
linoleic acid Hs - - - - -
clotrimazole Hs - - - - -
anandamide Hs - - - - -
Δ9-tetrahydrocannabinol Hs - - - - -
La3+ Hs - - - - -
ACAA Hs - - - - -
AMTB Hs - - - - - 12
[12]
cannabidiol Hs - - - - -
NADA Hs - - - - -
View species-specific channel blocker tables
Channel Blocker Comments
Compound M8-B has similar IC50 at the human TRPM8 expressed in CHO cells [1], and also shows inhibitory activity at mouse Trpm8 in a subset of primary somatosensory neurons [1]. It is unknown whether M8-B functions as a pore blocker or a gating inhibitor.
Tissue Distribution
Prostate
Species:  Human
Technique:  Northern Blot
References:  23
Prostate, testis, bladder > breast, thymus
Species:  Human
Technique:  RT-PCR
References:  23
Prostate, breast
Species:  Human
Technique:  In situ hybridisation
References:  23
Dorsal root ganglion
Species:  Mouse
Technique:  Northern Blot
References:  18
Dorsal root ganglion, trigeminal ganglion
Species:  Mouse
Technique:  In situ hybridisation
References:  18
Dorsal root ganglia, trigeminal ganglia
Species:  Rat
Technique:  Northern Blot
References:  15
Dorsal root ganglia, trigeminal ganglia
Species:  Rat
Technique:  In situ hybridisation
References:  15
Dorsal root ganglion, testis, prostate, bladder
Species:  Rat
Technique:  RT-PCR
References:  21
Tissue Distribution Comments
Genetically targeted reporter proteins (GFP-tagged) have been expressed via the Trmp8 promoter as an alternative means to examine putative channel expression [7,22].
Functional Assays
Patch-clamp analysis (whole-cell and single-channel recordings), intracellular Ca2+ imaging.
Species:  Rat
Tissue:  HEK cells transfected with a TRPM8 vector
Response measured:  Activation by cold, menthol icilin etc.
References:  15
Patch-clamp analysis (whole-cell and single-channel recordings), intracellular Ca2+ imaging.
Species:  Mouse
Tissue:  CHO cells transfected with a TRPM8 containing vector and Xenopus ooctyes injected with TRPM8 cRNA.
Response measured:  Activation by cold, menthol, and icilin
References:  18
Patch-clamp analysis (whole-cell and single-channel recordings).
Species:  Human
Tissue:  HEK cells transfected with a TRPM8 containing vector.
Response measured:  Activation by cold and menthol
References:  25
Patch-clamp analysis (whole-cell and single-channel recordings), intracellular Ca2+ imaging.
Species:  Rat
Tissue:  HEK cells transfected with a TRPM8 containing vector and xXenopus ooctyes injected with TRPM8 cRNA.
Response measured:  Activation by cold, menthol, and icilin
References:  15
Single channel recordings in planar lipid bilayers
Species:  Rat
Tissue:  Purified TRPM8 channels reconstituted into planar lipid bilayers
Response measured:  Activation by menthol
References:  27
Physiological Functions
A cold and cold-mimetic chemical receptor used for the detection of external stimuli.
Species:  Mouse
Tissue:  Dorsal root and trigeminal ganglia, as well as other sensory ganglia innervating internal tissues.
References:  3,6,8,15,18
Physiological Functions Comments
The physiological functions described are also found in rats, humans, avians, and amphibians.
Physiological Consequences of Altering Gene Expression
TRPM8-knockout mice have deficits in cold perception as determined by several behavioral assays.
Species:  Mouse
Tissue:  Sensory ganglia
Technique:  Gene targeting by homologous recombination
References:  3,6,8
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:2181435  MP:0004811 abnormal neuron physiology PMID: 17481392 
Trpm8tm1Apat Trpm8tm1Apat/Trpm8tm1Apat
involves: 129S1/Sv * C57BL/6
MGI:2181435  MP:0004811 abnormal neuron physiology PMID: 17481391 
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:2181435  MP:0002736 abnormal nociception after inflammation PMID: 17481392 
Trpm8tm1Apat Trpm8tm1Apat/Trpm8tm1Apat
involves: 129S1/Sv * C57BL/6
MGI:2181435  MP:0002736 abnormal nociception after inflammation PMID: 17481391 
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:2181435  MP:0001970 abnormal pain threshold PMID: 17481392 
Trpm8tm1Jul Trpm8tm1Jul/Trpm8tm1Jul
involves: 129P2/OlaHsd * C57BL/6
MGI:2181435  MP:0003663 abnormal thermosensation PMID: 17538622 
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:2181435  MP:0003663 abnormal thermosensation PMID: 17481392 
Trpm8tm1Apat Trpm8tm1Apat/Trpm8tm1Apat
involves: 129S1/Sv * C57BL/6
MGI:2181435  MP:0003663 abnormal thermosensation PMID: 17481391 
Trpm8tm1Jul Trpm8tm1Jul/Trpm8tm1Jul
involves: 129P2/OlaHsd * C57BL/6
MGI:2181435  MP:0001973 increased thermal nociceptive threshold PMID: 17538622 
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:2181435  MP:0001973 increased thermal nociceptive threshold PMID: 17481392 
Trpm8tm1Apat Trpm8tm1Apat/Trpm8tm1Apat
involves: 129S1/Sv * C57BL/6
MGI:2181435  MP:0001973 increased thermal nociceptive threshold PMID: 17481391 
Gene Expression and Pathophysiology
Up-regulated in adenocarcinomas.
Tissue or cell type:  Prostate as well as breast, colon, lung and skin
Pathophysiology:  Adenocarcinoma
Species:  Human
Technique:  In-situ hybridisation
References:  23

References

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1. Almeida MC, Hew-Butler T, Soriano RN, Rao S, Wang W, Wang J, Tamayo N, Oliveira DL, Nucci TB, Aryal P et al.. (2012) Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature. J. Neurosci., 32 (6): 2086-99. [PMID:22323721]

2. Andersson DA, Chase HW, Bevan S. (2004) TRPM8 activation by menthol, icilin, and cold is differentially modulated by intracellular pH. J. Neurosci., 24 (23): 5364-9. [PMID:15190109]

3. Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D. (2007) The menthol receptor TRPM8 is the principal detector of environmental cold. Nature, 448 (7150): 204-8. [PMID:17538622]

4. Behrendt HJ, Germann T, Gillen C, Hatt H, Jostock R. (2004) Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br. J. Pharmacol., 141 (4): 737-45. [PMID:14757700]

5. Brauchi S, Orio P, Latorre R. (2004) Clues to understanding cold sensation: thermodynamics and electrophysiological analysis of the cold receptor TRPM8. Proc. Natl. Acad. Sci. U.S.A., 101 (43): 15494-9. [PMID:15492228]

6. Colburn RW, Lubin ML, Stone DJ, Wang Y, Lawrence D, D'Andrea MR, Brandt MR, Liu Y, Flores CM, Qin N. (2007) Attenuated cold sensitivity in TRPM8 null mice. Neuron, 54 (3): 379-86. [PMID:17481392]

7. Dhaka A, Earley TJ, Watson J, Patapoutian A. (2008) Visualizing cold spots: TRPM8-expressing sensory neurons and their projections. J. Neurosci., 28 (3): 566-75. [PMID:18199758]

8. Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A. (2007) TRPM8 is required for cold sensation in mice. Neuron, 54 (3): 371-8. [PMID:17481391]

9. Hu HZ, Gu Q, Wang C, Colton CK, Tang J, Kinoshita-Kawada M, Lee LY, Wood JD, Zhu MX. (2004) 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J. Biol. Chem., 279 (34): 35741-8. [PMID:15194687]

10. Hui K, Guo Y, Feng ZP. (2005) Biophysical properties of menthol-activated cold receptor TRPM8 channels. Biochem. Biophys. Res. Commun., 333 (2): 374-82. [PMID:15950184]

11. Knowlton WM, Daniels RL, Palkar R, McCoy DD, McKemy DD. (2011) Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice. PLoS ONE, 6 (9): e25894. [PMID:21984952]

12. Lashinger ES, Steiginga MS, Hieble JP, Leon LA, Gardner SD, Nagilla R, Davenport EA, Hoffman BE, Laping NJ, Su X. (2008) AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome. Am. J. Physiol. Renal Physiol., 295 (3): F803-10. [PMID:18562636]

13. Ma S, G G, Ak VE, Jf D, H H. (2008) Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. Pak J Pharm Sci, 21 (4): 370-8. [PMID:18930858]

14. Madrid R, Donovan-Rodríguez T, Meseguer V, Acosta MC, Belmonte C, Viana F. (2006) Contribution of TRPM8 channels to cold transduction in primary sensory neurons and peripheral nerve terminals. J. Neurosci., 26 (48): 12512-25. [PMID:17135413]

15. McKemy DD, Neuhausser WM, Julius D. (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature, 416 (6876): 52-8. [PMID:11882888]

16. Myers BR, Sigal YM, Julius D. (2009) Evolution of thermal response properties in a cold-activated TRP channel. PLoS ONE, 4 (5): e5741. [PMID:19492038]

17. Naziroğlu M, Ozgül C. (2012) Effects of antagonists and heat on TRPM8 channel currents in dorsal root ganglion neuron activated by nociceptive cold stress and menthol. Neurochem. Res., 37 (2): 314-20. [PMID:21964764]

18. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. (2002) A TRP channel that senses cold stimuli and menthol. Cell, 108 (5): 705-15. [PMID:11893340]

19. Rohács T, Lopes CM, Michailidis I, Logothetis DE. (2005) PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nat. Neurosci., 8 (5): 626-34. [PMID:15852009]

20. Sherkheli MA, Vogt-Eisele AK, Bura D, Beltrán Márques LR, Gisselmann G, Hatt H. (2010) Characterization of selective TRPM8 ligands and their structure activity response (S.A.R) relationship. J Pharm Pharm Sci, 13 (2): 242-53. [PMID:20816009]

21. Stein RJ, Santos S, Nagatomi J, Hayashi Y, Minnery BS, Xavier M, Patel AS, Nelson JB, Futrell WJ, Yoshimura N, Chancellor MB, De Miguel F. (2004) Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. J. Urol., 172 (3): 1175-8. [PMID:15311065]

22. Takashima Y, Daniels RL, Knowlton W, Teng J, Liman ER, McKemy DD. (2007) Diversity in the neural circuitry of cold sensing revealed by genetic axonal labeling of transient receptor potential melastatin 8 neurons. J. Neurosci., 27 (51): 14147-57. [PMID:18094254]

23. Tsavaler L, Shapero MH, Morkowski S, Laus R. (2001) Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res., 61 (9): 3760-9. [PMID:11325849]

24. Tsuzuki Y, Sawamoto D, Sakamoto T, Kato T, Niwa Y, Awai N. (2012) Sulfonamide compounds having trpm8 antagonistic activity. Patent number: WO2012124825. Assignee: Mitsubishi Tanabe Pharma Corporation. Priority date: 16/03/2011. Publication date: 20/09/2012.

25. Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B. (2004) The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature, 430 (7001): 748-54. [PMID:15306801]

26. Yin Y, Wu M, Zubcevic L, Borschel WF, Lander GC, Lee SY. (2018) Structure of the cold- and menthol-sensing ion channel TRPM8. Science, 359 (6372): 237-241. [PMID:29217583]

27. Zakharian E, Thyagarajan B, French RJ, Pavlov E, Rohacs T. (2009) Inorganic polyphosphate modulates TRPM8 channels. PLoS ONE, 4 (4): e5404. [PMID:19404398]

28. Zhang X, Mak S, Li L, Parra A, Denlinger B, Belmonte C, McNaughton PA. (2012) Direct inhibition of the cold-activated TRPM8 ion channel by Gαq. Nat. Cell Biol., 14 (8): 851-8. [PMID:22750945]

Contributors

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How to cite this page

David McKemy, David E. Clapham.
Transient Receptor Potential channels: TRPM8. Last modified on 12/07/2018. Accessed on 26/09/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=500.