K<SUB>v</SUB>4.2 | Voltage-gated potassium channels | IUPHAR/BPS Guide to PHARMACOLOGY

Kv4.2

Target id: 553

Nomenclature: Kv4.2

Family: Voltage-gated potassium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for Kv4.2 in GtoImmuPdb

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 630 7q31 KCND2 potassium voltage-gated channel subfamily D member 2 21,49
Mouse 6 1 630 6 A2-A3.1 Kcnd2 potassium voltage-gated channel, Shal-related family, member 2 18
Rat 6 1 630 4q22 Kcnd2 potassium voltage-gated channel subfamily D member 2 4
Previous and Unofficial Names
Potassium voltage-gated channel subfamily D member 2 | RK5 | potassium voltage-gated channel, Shal-related subfamily, member 2 | potassium channel, voltage gated Shal related subfamily D, member 2 | potassium channel, voltage-gated Shal-related subfamily D, member 2 | potassium voltage-gated channel, Shal-related family, member 2 | potassium voltage-gated channel
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Kv4.3 15
Auxiliary Subunits
Name References
KChIP 1-4 2,12,17,25,28,37
Frequenin, NCS-1 16,30
DPPX, DPP10 22,28-29,39,48
Navβ1 27
Other Associated Proteins
Name References
Filamin 31
MinK-related Peptide 1 31
Aβ peptide 33
Functional Characteristics
KA
Ion Selectivity and Conductance
Species:  Rat
Rank order:  K+ [10000.0 pS] > Na+ [10.0 pS] > Cl- [1.0 pS]
References:  4
Species:  Rat
Macroscopic current rectification:  A-Type current
References:  4
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  - - COS-7 Rat
Inactivation  - 44.0 – 4.3 34
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  0.1 - 22 Xenopus laevis oocytes Mouse
Inactivation  -64.0 200.0 22
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -1.0 - 4 Xenopus laevis oocytes Rat
Inactivation  - 15.0 – 61.0 4
Comments  Rapid inactivation
Associated subunits (Human)
KChIP 1-4, DPP6, DPP10, Kvβ1, NCS-1, Navβ1

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

Gating Inhibitor Comments
UO126 suppresses rat Kv4.2-mediated K+ currents and accelerates current decay in transfected CHO cells [47].
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
phrixotoxin 1 Mm - 7.1 – 8.3 pIC50 - - 8-9
pIC50 7.1 – 8.3 [8-9]
phrixotoxin 2 Mm - 7.1 – 8.3 pIC50 - - 8-9
pIC50 7.1 – 8.3 [8-9]
heteropodatoxin-2 Rn - 6.5 pIC50 - - 11,36,43
pIC50 6.5 [11,36,43]
sBmTX 3 Rn - 6.0 pIC50 - - 43
pIC50 6.0 [43]
arachidonic acid Rn - 5.7 pIC50 - - 44-45
pIC50 5.7 [44-45]
quinidine Rn - 4.9 pIC50 - - 7
pIC50 4.9 [7]
fampridine Mm - 2.3 pIC50 - - 13
pIC50 2.3 [13]
View species-specific channel blocker tables
Channel Blocker Comments
Kv4.2 was relatively insensitive to TEA and also to DABCO (1,4 - Diazabicyclo[2.2.2] octane) derivatives, showing 3% block with 100 µM JE188, 3% block with 1 mM TG27, and 38% block with 0.5 mM JC638.2 [13]
Tissue Distribution
Brain (cerebellum > hippocampus, thalamus, medial habenular nucleus, cerebral cortex; basal ganglai, forebrain), uterus. Expression is very low or absent in other tissues.
Species:  Rat
Technique:  RT-PCR
References:  5,31,35,40,46
Functional Assays
Patch-clamp technique
Species:  Rat
Tissue:  Xenopus laevis oocytes, CHO cells
Response measured:  Transient, voltage-sensitive A-type potassium current
References:  19
Patch-clamp technique
Species:  None
Tissue:  COS-7 cells
Response measured:  Transient, voltage-sensitive A-type potassium current
References:  1
Voltage clamp
Species:  Mouse
Tissue:  Xenopus laevis oocytes
Response measured:  Transient, voltage-sensitive A-type current
References:  22
Whole-cell patch-clamp technique
Species:  Human
Tissue:  HEK293 cells
Response measured:  Transient, voltage-sensitive A-type potassium current
References:  6,10
Patch-clamp technique
Species:  Human
Tissue:  HEK293 cells
Response measured:  Transient, voltage-sensitive A-type potassium current
References:  23,49
Physiological Functions
Kv4.2 regulates A-type K+ current and mediates the generation of action potential, dampening back-propogating action potentials in CA1 hippocampal neurons.
Species:  Mouse
Tissue:  Brain, cortex
References:  8,32
Kv4.2 contributes to ITO current in heart and mediates the repolarisation of the cardiac action potential (notch phase).
Species:  Mouse
Tissue:  Heart
References:  3,14
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnd2tm1Jmn Kcnd2tm1Jmn/Kcnd2tm1Jmn
involves: 129S1/Sv * 129X1/SvJ
MGI:102663  MP:0003484 abnormal channel response PMID: 16600858 
Kcnd2tm1Jmn Kcnd2tm1Jmn/Kcnd2tm1Jmn
FVB.129-Kcnd2
MGI:102663  MP:0003484 abnormal channel response PMID: 16293790 
Kcnd2tm1Jmn Kcnd2tm1Jmn/Kcnd2tm1Jmn
involves: 129S1/Sv * 129X1/SvJ
MGI:102663  MP:0002882 abnormal neuron morphology PMID: 16600858 
Kcnd2tm1Jmn Kcnd2tm1Jmn/Kcnd2tm1Jmn
FVB.129-Kcnd2
MGI:102663  MP:0002736 abnormal nociception after inflammation PMID: 16600858 
Kcnd2tm1Jmn Kcnd2tm1Jmn/Kcnd2tm1Jmn
involves: 129S1/Sv * 129X1/SvJ
MGI:102663  MP:0003998 decreased thermal nociceptive threshold PMID: 16600858 
Kcnd2tm1Jmn Kcnd2tm1Jmn/Kcnd2tm1Jmn
involves: 129S1/Sv * 129X1/SvJ
MGI:102663  MP:0002738 hyperresponsive to tactile stimuli PMID: 16600858 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Epilepsy and Autism
References:  24
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense, gain of function Human V404M 24
Disease:  Temporal lobe epilepsy
Disease Ontology: DOID:3328
References:  38
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Truncation, loss of function Human N587fsX1 c.2723_2727delAAACT The mutation leads to a prematurely truncated protein with loss of function 38
Gene Expression and Pathophysiology
Transient reduction in Kv4.2 mRNA levels in the granule cell layer of the dentate gyrus following pentylenetetrazole induced generalized seizures.
Tissue or cell type:  Brain
Pathophysiology:  Seizures
Species:  Rat
Technique:  RT-PCR
References:  42
Decrease of Kv4.2 expression in ventricles of renovascular hypertensive rats.
Tissue or cell type:  Ventricles.
Pathophysiology:  Hypertension, heart failure.
Species:  Rat
Technique:  RT-PCR
References:  41
Kv4.2 protein expression and trafficking processes were altered by Aβ
Tissue or cell type:  HEK293
Pathophysiology:  Cell death and damage induced by Aβ
Species:  Rat
Technique:  Western Blotting, immunohistochemistry
References:  33
Knock-out (Kv4.2 -/-)
Tissue or cell type:  in vivo
Pathophysiology:  Enhanced sensitivity to tactile and thermal stimuli
Species:  Mouse
Technique: 
References:  20
Knock-out (Kv4.2 -/-)
Tissue or cell type:  Heart
Pathophysiology:  Loss of cardiac Ito; action potential and QT prolongation
Species:  Mouse
Technique: 
References:  14,26
Knock-out (Kv4.2 -/-)
Tissue or cell type:  Cortical pyramidal neurons
Pathophysiology:  Attenuation of IA; increase in Rin; action potential prolongation; altered repetitive firing
Species:  Mouse
Technique: 
References:  8,32
General Comments
Kv4.2 is a member of the mammalian Shal-related family.

The Kv4.2 (KCND2) gene, like KCND1 and KCND3, contains six exons, although the introns are significantly longer in KCND2.

The kinetic properties depend on the expression system, recording configuration, and the presence of auxiliary subunits (KChIPs).

Kv4.2 currents expressed in Xenopus laevis oocytes are suppressed in response to protein kinase C activation.

References

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1. Adams JP, Anderson AE, Varga AW, Dineley KT, Cook RG, Pfaffinger PJ, Sweatt JD. (2000) The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK. J. Neurochem., 75 (6): 2277-87. [PMID:11080179]

2. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS et al.. (2000) Modulation of A-type potassium channels by a family of calcium sensors. Nature, 403 (6769): 553-6. [PMID:10676964]

3. Barry DM, Xu H, Schuessler RB, Nerbonne JM. (1998) Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit. Circ. Res., 83 (5): 560-7. [PMID:9734479]

4. Blair TA, Roberds SL, Tamkun MM, Hartshorne RP. (1991) Functional characterization of RK5, a voltage-gated K+ channel cloned from the rat cardiovascular system. FEBS Lett., 295 (1-3): 211-3. [PMID:1722463]

5. Brundel BJ, Van Gelder IC, Henning RH, Tuinenburg AE, Wietses M, Grandjean JG, Wilde AA, Van Gilst WH, Crijns HJ. (2001) Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K+ channels. J. Am. Coll. Cardiol., 37 (3): 926-32. [PMID:11693772]

6. Bähring R, Boland LM, Varghese A, Gebauer M, Pongs O. (2001) Kinetic analysis of open- and closed-state inactivation transitions in human Kv4.2 A-type potassium channels. J. Physiol. (Lond.), 535 (Pt 1): 65-81. [PMID:11507158]

7. Caballero R, Pourrier M, Schram G, Delpón E, Tamargo J, Nattel S. (2003) Effects of flecainide and quinidine on Kv4.2 currents: voltage dependence and role of S6 valines. Br. J. Pharmacol., 138 (8): 1475-84. [PMID:12721103]

8. Carrasquillo Y, Burkhalter A, Nerbonne JM. (2012) A-type K+ channels encoded by Kv4.2, Kv4.3 and Kv1.4 differentially regulate intrinsic excitability of cortical pyramidal neurons. J. Physiol. (Lond.), 590 (Pt 16): 3877-90. [PMID:22615428]

9. Chagot B, Escoubas P, Villegas E, Bernard C, Ferrat G, Corzo G, Lazdunski M, Darbon H. (2004) Solution structure of Phrixotoxin 1, a specific peptide inhibitor of Kv4 potassium channels from the venom of the theraphosid spider Phrixotrichus auratus. Protein Sci., 13 (5): 1197-208. [PMID:15096626]

10. Diochot S, Drici MD, Moinier D, Fink M, Lazdunski M. (1999) Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis. Br. J. Pharmacol., 126 (1): 251-63. [PMID:10051143]

11. Ebbinghaus J, Legros C, Nolting A, Guette C, Celerier ML, Pongs O, Bähring R. (2004) Modulation of Kv4.2 channels by a peptide isolated from the venom of the giant bird-eating tarantula Theraphosa leblondi. Toxicon, 43 (8): 923-32. [PMID:15208026]

12. Foeger NC, Wang W, Mellor RL, Nerbonne JM. (2013) Stabilization of Kv4 protein by the accessory K(+) channel interacting protein 2 (KChIP2) subunit is required for the generation of native myocardial fast transient outward K(+) currents. J. Physiol. (Lond.), 591 (Pt 17): 4149-66. [PMID:23713033]

13. Gordon E, Cohen JL, Engel R, Abbott GW. (2006) 1,4-Diazabicyclo[2.2.2]octane derivatives: a novel class of voltage-gated potassium channel blockers. Mol. Pharmacol., 69 (3): 718-26. [PMID:16317109]

14. Guo W, Jung WE, Marionneau C, Aimond F, Xu H, Yamada KA, Schwarz TL, Demolombe S, Nerbonne JM. (2005) Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction. Circ. Res., 97 (12): 1342-50. [PMID:16293790]

15. Guo W, Li H, Aimond F, Johns DC, Rhodes KJ, Trimmer JS, Nerbonne JM. (2002) Role of heteromultimers in the generation of myocardial transient outward K+ currents. Circ. Res., 90 (5): 586-93. [PMID:11909823]

16. Guo W, Malin SA, Johns DC, Jeromin A, Nerbonne JM. (2002) Modulation of Kv4-encoded K(+) currents in the mammalian myocardium by neuronal calcium sensor-1. J. Biol. Chem., 277 (29): 26436-43. [PMID:11994284]

17. Han W, Nattel S, Noguchi T, Shrier A. (2006) C-terminal domain of Kv4.2 and associated KChIP2 interactions regulate functional expression and gating of Kv4.2. J. Biol. Chem., 281 (37): 27134-44. [PMID:16820361]

18. Harrell MD, Harbi S, Hoffman JF, Zavadil J, Coetzee WA. (2007) Large-scale analysis of ion channel gene expression in the mouse heart during perinatal development. Physiol. Genomics, 28 (3): 273-83. [PMID:16985003]

19. Holmqvist MH, Cao J, Knoppers MH, Jurman ME, Distefano PS, Rhodes KJ, Xie Y, An WF. (2001) Kinetic modulation of Kv4-mediated A-current by arachidonic acid is dependent on potassium channel interacting proteins. J. Neurosci., 21 (12): 4154-61. [PMID:11404400]

20. Hu HJ, Carrasquillo Y, Karim F, Jung WE, Nerbonne JM, Schwarz TL, Gereau RW. (2006) The kv4.2 potassium channel subunit is required for pain plasticity. Neuron, 50 (1): 89-100. [PMID:16600858]

21. Isbrandt D, Leicher T, Waldschütz R, Zhu X, Luhmann U, Michel U, Sauter K, Pongs O. (2000) Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(TO) and I(SA). Genomics, 64 (2): 144-54. [PMID:10729221]

22. Jerng HH, Qian Y, Pfaffinger PJ. (2004) Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10). Biophys. J., 87 (4): 2380-96. [PMID:15454437]

23. Jin HW, Zhang W, Qu LT, Wang XL. (2003) [Electrophysiological correspondence between Kv4.2 current and transient outward potassium current in the cultured rat hippocampal neuron]. Sheng Li Xue Bao, 55 (6): 711-6. [PMID:14695490]

24. Lee H, Lin MC, Kornblum HI, Papazian DM, Nelson SF. (2014) Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum. Mol. Genet., 23 (13): 3481-9. [PMID:24501278]

25. Lin YL, Chen CY, Cheng CP, Chang LS. (2004) Protein-protein interactions of KChIP proteins and Kv4.2. Biochem. Biophys. Res. Commun., 321 (3): 606-10. [PMID:15358149]

26. London B, Baker LC, Petkova-Kirova P, Nerbonne JM, Choi BR, Salama G. (2007) Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT. J. Physiol. (Lond.), 578 (Pt 1): 115-29. [PMID:17110412]

27. Marionneau C, Carrasquillo Y, Norris AJ, Townsend RR, Isom LL, Link AJ, Nerbonne JM. (2012) The sodium channel accessory subunit Navβ1 regulates neuronal excitability through modulation of repolarizing voltage-gated K⁺ channels. J. Neurosci., 32 (17): 5716-27. [PMID:22539834]

28. Marionneau C, LeDuc RD, Rohrs HW, Link AJ, Townsend RR, Nerbonne JM. (2009) Proteomic analyses of native brain K(V)4.2 channel complexes. Channels (Austin), 3 (4): 284-94. [PMID:19713751]

29. Nadal MS, Ozaita A, Amarillo Y, Vega-Saenz de Miera E, Ma Y, Mo W, Goldberg EM, Misumi Y, Ikehara Y, Neubert TA et al.. (2003) The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels. Neuron, 37 (3): 449-61. [PMID:12575952]

30. Nakamura TY, Sturm E, Pountney DJ, Orenzoff B, Artman M, Coetzee WA. (2003) Developmental expression of NCS-1 (frequenin), a regulator of Kv4 K+ channels, in mouse heart. Pediatr. Res., 53 (4): 554-7. [PMID:12612193]

31. Nerbonne JM. (2000) Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J. Physiol. (Lond.), 525 Pt 2: 285-98. [PMID:10835033]

32. Norris AJ, Nerbonne JM. (2010) Molecular dissection of I(A) in cortical pyramidal neurons reveals three distinct components encoded by Kv4.2, Kv4.3, and Kv1.4 alpha-subunits. J. Neurosci., 30 (14): 5092-101. [PMID:20371829]

33. Plant LD, Webster NJ, Boyle JP, Ramsden M, Freir DB, Peers C, Pearson HA. (2006) Amyloid beta peptide as a physiological modulator of neuronal 'A'-type K+ current. Neurobiol. Aging, 27 (11): 1673-83. [PMID:16271805]

34. Pourrier M, Herrera D, Caballero R, Schram G, Wang Z, Nattel S. (2004) The Kv4.2 N-terminal restores fast inactivation and confers KChlP2 modulatory effects on N-terminal-deleted Kv1.4 channels. Pflugers Arch., 449 (3): 235-47. [PMID:15452711]

35. Roberds SL, Tamkun MM. (1991) Cloning and tissue-specific expression of five voltage-gated potassium channel cDNAs expressed in rat heart. Proc. Natl. Acad. Sci. U.S.A., 88 (5): 1798-802. [PMID:1705709]

36. Sanguinetti MC, Johnson JH, Hammerland LG, Kelbaugh PR, Volkmann RA, Saccomano NA, Mueller AL. (1997) Heteropodatoxins: peptides isolated from spider venom that block Kv4.2 potassium channels. Mol. Pharmacol., 51 (3): 491-8. [PMID:9058605]

37. Shibata R, Misonou H, Campomanes CR, Anderson AE, Schrader LA, Doliveira LC, Carroll KI, Sweatt JD, Rhodes KJ, Trimmer JS. (2003) A fundamental role for KChIPs in determining the molecular properties and trafficking of Kv4.2 potassium channels. J. Biol. Chem., 278 (38): 36445-54. [PMID:12829703]

38. Singh B, Ogiwara I, Kaneda M, Tokonami N, Mazaki E, Baba K, Matsuda K, Inoue Y, Yamakawa K. (2006) A Kv4.2 truncation mutation in a patient with temporal lobe epilepsy. Neurobiol. Dis., 24 (2): 245-53. [PMID:16934482]

39. Strop P, Bankovich AJ, Hansen KC, Garcia KC, Brunger AT. (2004) Structure of a human A-type potassium channel interacting protein DPPX, a member of the dipeptidyl aminopeptidase family. J. Mol. Biol., 343 (4): 1055-65. [PMID:15476821]

40. Suzuki T, Takimoto K. (2005) Differential expression of Kv4 pore-forming and KChIP auxiliary subunits in rat uterus during pregnancy. Am. J. Physiol. Endocrinol. Metab., 288 (2): E335-41. [PMID:15454398]

41. Takimoto K, Li D, Hershman KM, Li P, Jackson EK, Levitan ES. (1997) Decreased expression of Kv4.2 and novel Kv4.3 K+ channel subunit mRNAs in ventricles of renovascular hypertensive rats. Circ. Res., 81 (4): 533-9. [PMID:9314834]

42. Tsaur ML, Sheng M, Lowenstein DH, Jan YN, Jan LY. (1992) Differential expression of K+ channel mRNAs in the rat brain and down-regulation in the hippocampus following seizures. Neuron, 8 (6): 1055-67. [PMID:1610565]

43. Vacher H, Diochot S, Bougis PE, Martin-Eauclaire MF, Mourre C. (2006) Kv4 channels sensitive to BmTX3 in rat nervous system: autoradiographic analysis of their distribution during brain ontogenesis. Eur. J. Neurosci., 24 (5): 1325-40. [PMID:16987219]

44. Villarroel A, Schwarz TL. (1996) Inhibition of the Kv4 (Shal) family of transient K+ currents by arachidonic acid. J. Neurosci., 16 (8): 2522-32. [PMID:8786428]

45. Wang H, Shi H, Wang Z. (1999) Nicotine depresses the functions of multiple cardiac potassium channels. Life Sci., 65 (12): PL143-9. [PMID:10503950]

46. Wickenden AD, Jegla TJ, Kaprielian R, Backx PH. (1999) Regional contributions of Kv1.4, Kv4.2, and Kv4.3 to transient outward K+ current in rat ventricle. Am. J. Physiol., 276 (5 Pt 2): H1599-607. [PMID:10330244]

47. Yuan LL, Chen X, Kunjilwar K, Pfaffinger P, Johnston D. (2006) Acceleration of K+ channel inactivation by MEK inhibitor U0126. Am. J. Physiol., Cell Physiol., 290 (1): C165-71. [PMID:16135544]

48. Zagha E, Ozaita A, Chang SY, Nadal MS, Lin U, Saganich MJ, McCormack T, Akinsanya KO, Qi SY, Rudy B. (2005) DPP10 modulates Kv4-mediated A-type potassium channels. J. Biol. Chem., 280 (19): 18853-61. [PMID:15671030]

49. Zhu XR, Wulf A, Schwarz M, Isbrandt D, Pongs O. (1999) Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current. Recept. Channels, 6 (5): 387-400. [PMID:10551270]

Contributors

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How to cite this page

Jeanne Nerbonne, Bernardo Rudy, K. George Chandy, Stephan Grissmer, George A. Gutman, Michel Lazdunski, David Mckinnon, Luis A. Pardo, Gail A. Robertson, Michael C. Sanguinetti, Walter Stühmer, Xiaoliang Wang.
Voltage-gated potassium channels: Kv4.2. Last modified on 26/10/2015. Accessed on 18/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=553.