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5-HT3AB

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Target not currently curated in GtoImmuPdb

Target id: 378

Nomenclature: 5-HT3AB

Family: 5-HT3 receptors

Quaternary Structure: Subunits
5-HT3A
5-HT3B
Previous and Unofficial Names Click here for help
5-HT3A/B
Functional Characteristics Click here for help
γ = 0.4-0.8 pS [+ 5-HT3B, γ = 16 pS]; inwardly rectifying current [+ 5-HT3B, rectification reduced]; nH 2-3 [+ 5-HT3B 1-2]; relative permeability to divalent cations reduced by co-expression of the 5-HT3B subunit
Ion Selectivity and Conductance Click here for help
Species:  Human
Rank order:  Na+ = K+ = Cs+ > Ca2+
References:  5
Species:  Human Rat
Single channel conductance (pS):  16 (outside-out patch), 30 (cell-attached patch) 7-14
References:  5,11 7
Species:  Human Rat
Single channel current rectification:  Linear Inward
References:  5 7
Species:  Human Rat
Macroscopic current rectification:  Linear Inward
References:  5,8 7
Ion Selectivity and Conductance Comments
For the human receptor PCa/PCs = 0.62, PMg/PCs = 0 [5]. The fractional calcium flux (Ca2+ PF) is 2.0% [12].
Human channels can also show mildly inward macroscopic current rectification [8].
Natural/Endogenous Ligands Click here for help
5-hydroxytryptamine

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
quipazine Small molecule or natural product Click here for species-specific activity table Hs Agonist 9.0 pKi 1
pKi 9.0 [1]
CSTI-300 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 8.8 pKi 13
pKi 8.8 (Ki 1.59x10-9 M) [13]
meta-chlorphenylbiguanide Small molecule or natural product Click here for species-specific activity table Hs Agonist 7.0 pKi 1
pKi 7.0 [1]
5-hydroxytryptamine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 6.0 pKi 1
pKi 6.0 [1]
1-phenylbiguanide Small molecule or natural product Click here for species-specific activity table Hs Agonist 4.9 pKi 1
pKi 4.9 [1]
meta-chlorphenylbiguanide Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.7 pEC50 5
pEC50 5.7 [5]
5-hydroxytryptamine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 4.8 – 5.8 pEC50 2,5-6,15
pEC50 4.8 – 5.8 [2,5-6,15]
2-methyl-5-HT Small molecule or natural product Click here for species-specific activity table Hs Agonist 4.9 pEC50 5
pEC50 4.9 [5]
Agonist Comments
Apparent affinities of agonists are for ligand binding to the recombinant 5-HT3AB receptor expressed in mammalian cells, or pEC50 values determined under voltage-clamp for the receptor expressed in Xenopus laevis oocytes. Selectivity refers to the 5-HT3 receptor family: the agents listed do not discriminate between 5-HT3A and 5-HT3AB receptors, although in some cases they demonstrate lower potency at the latter. Comments concerning efficacy relate to data obtained from voltage-clamp studies of the human 5-HT3AB receptor expressed in Xenopus laevis oocytes and from Ca2+ imaging studies of the receptor expressed in HEK 293 cells [6].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]granisetron Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 8.8 pKd 1
pKd 8.8 [1]
(S)-zacopride Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.8 pKi 1
pKi 8.8 [1]
azasetron Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.4 pKi 1
pKi 8.4 [1]
ondansetron Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.8 pKi 1
pKi 7.8 [1]
(R)-zacopride Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.7 pKi 1
pKi 7.7 [1]
metoclopramide Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 5.7 pKi 1
pKi 5.7 [1]
cocaine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 4.8 pKi 1
pKi 4.8 [1]
tubocurarine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 4.5 pKi 1
pKi 4.5 [1]
Antagonist Comments
Data tabulated are for ligand binding to the human recombinant 5-HT3AB receptor expressed in mammalian cells. Selectivity refers to the 5-HT3 receptor family: the agents listed do not discriminate between 5-HT3A and 5-HT3AB receptor subtypes in radioligand binding studies. However, in electrophysiological studies, (+)-tubocurarine demonstrates modest selectivity for human 5-HT3A (IC50 = 3μM) versus human 5-HT3AB (IC50 = 14-21μM) receptors [5]. A more potent blockade by (+)-tubocurarine, although with reduced selectivity, is apparent for the rat 5-HT3A and 5-HT3AB receptors [7].
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
picrotoxinin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - no 4.2 pIC50 - no 16
pIC50 4.2 (IC50 6.3x10-5 M) [16]
Not voltage dependent
picrotoxin Small molecule or natural product Click here for species-specific activity table Mm - yes 2.9 pIC50 - no 3-4
pIC50 2.9 [3-4]
Not voltage dependent
bilobalide Small molecule or natural product Click here for species-specific activity table Hs - no 2.5 pIC50 - no 16
pIC50 2.5 (IC50 3.1x10-3 M) [16]
Not voltage dependent
ginkgolide B Small molecule or natural product Click here for species-specific activity table Hs - no 2.4 pIC50 - no 16
pIC50 2.4 (IC50 3.9x10-3 M) [16]
Not voltage dependent
View species-specific channel blocker tables
Channel Blocker Comments
Although picrotoxin is approximately 27-less more potent in blocking mouse 5-HT3AB versus mouse 5-HT3A receptors, the degree of discrimination between equivalent human receptor orthologues is substantially smaller, most probably due to differences in the structure of the TM2 domain [4].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
trichloroethanol Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Mm Positive - - 2.5x10-4 - 1x10-2 no 9
Conc range: 2.5x10-4 - 1x10-2 M increased rate of channel activation [9]
Not voltage dependent
Allosteric Modulator Comments
Ethanol is a positive allosteric modulator of the 5-HT3A receptor but, at concentrations up to 200 mM, has no effect on currents mediated by the 5-HT3AB receptor [9]. Chloroform, halothane and small volume n-alcohols enhance the gating of 5-HT3A receptors and incorporation of the 5-HT3B subunit to form 5-HT3AB receptors suppresses this action [14-15].
Functional Assays Click here for help
Measurement of cation current in Xenopus oocytes expressing both the 5-HT3A and 5-HT3B subunits.
Species:  Human
Tissue:  Xenopus laevis oocytes
Response measured:  Cation current under voltage-clamp.
References:  5-6
Measurement of intracellular Ca2+ increase using a Flexstation in HEK 293 cells transfected with the 5-HT3A and 5-HT3B subunits.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Ca2+-sensitive change in fluorescence.
References:  6
Measurement of Ca2+-induced aequorin luminescence in HEK-293 cells co-transfected with the 5-HT3A and 5-HT3B subunits and aequorin.
Species:  Human
Tissue:  HEK-293 cells
Response measured:  Ca2+-sensitive change in fluorescence.
References:  17
Measurement of cation current in HEK 293 cells transfected with both 5-HT3A and 5-HT3B subunits.
Species:  Human
Tissue:  HEK 293 cells
Response measured:  Cation current under voltage-clamp.
References:  5,10-11

References

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1. Brady CA, Stanford IM, Ali I, Lin L, Williams JM, Dubin AE, Hope AG, Barnes NM. (2001) Pharmacological comparison of human homomeric 5-HT3A receptors versus heteromeric 5-HT3A/3B receptors. Neuropharmacology, 41 (2): 282-4. [PMID:11489465]

2. Dang H, England PM, Farivar SS, Dougherty DA, Lester HA. (2000) Probing the role of a conserved M1 proline residue in 5-hydroxytryptamine(3) receptor gating. Mol. Pharmacol., 57 (6): 1114-22. [PMID:10825381]

3. Das P, Dillon GH. (2003) The 5-HT3B subunit confers reduced sensitivity to picrotoxin when co-expressed with the 5-HT3A receptor. Brain Res. Mol. Brain Res., 119 (2): 207-12. [PMID:14625088]

4. Das P, Dillon GH. (2005) Molecular determinants of picrotoxin inhibition of 5-hydroxytryptamine type 3 receptors. J. Pharmacol. Exp. Ther., 314 (1): 320-8. [PMID:15814570]

5. Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF. (1999) The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature, 397 (6717): 359-63. [PMID:9950429]

6. Dubin AE, Huvar R, D'Andrea MR, Pyati J, Zhu JY, Joy KC, Wilson SJ, Galindo JE, Glass CA, Luo L et al.. (1999) The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit. J. Biol. Chem., 274 (43): 30799-810. [PMID:10521471]

7. Hanna MC, Davies PA, Hales TG, Kirkness EF. (2000) Evidence for expression of heteromeric serotonin 5-HT(3) receptors in rodents. J. Neurochem., 75 (1): 240-7. [PMID:10854267]

8. Hapfelmeier G, Tredt C, Haseneder R, Zieglgänsberger W, Eisensamer B, Rupprecht R, Rammes G. (2003) Co-expression of the 5-HT3B serotonin receptor subunit alters the biophysics of the 5-HT3 receptor. Biophys. J., 84 (3): 1720-33. [PMID:12609874]

9. Hayrapetyan V, Jenschke M, Dillon GH, Machu TK. (2005) Co-expression of the 5-HT(3B) subunit with the 5-HT(3A) receptor reduces alcohol sensitivity. Brain Res. Mol. Brain Res., 142 (2): 146-50. [PMID:16257471]

10. Kelley SP, Dunlop JI, Kirkness EF, Lambert JJ, Peters JA. (2003) A cytoplasmic region determines single-channel conductance in 5-HT3 receptors. Nature, 424 (6946): 321-4. [PMID:12867984]

11. Krzywkowski K, Davies PA, Feinberg-Zadek PL, Bräuner-Osborne H, Jensen AA. (2008) High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor. Proc. Natl. Acad. Sci. U.S.A., 105 (2): 722-7. [PMID:18184810]

12. Noam Y, Wadman WJ, van Hooft JA. (2008) On the voltage-dependent Ca2+ block of serotonin 5-HT3 receptors: a critical role of intracellular phosphates. J. Physiol. (Lond.), 586 (15): 3629-38. [PMID:18566001]

13. Roberts A, Grafton G, Powell AD, Brock K, Chen C, Xie D, Huang J, Liu S, Cooper AJ, Brady CA et al.. (2020) CSTI-300 (SMP-100); a Novel 5-HT3 Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome. J. Pharmacol. Exp. Ther., 373 (1): 122-134. [PMID:32102919]

14. Rüsch D, Musset B, Wulf H, Schuster A, Raines DE. (2007) Subunit-dependent modulation of the 5-hydroxytryptamine type 3 receptor open-close equilibrium by n-alcohols. J. Pharmacol. Exp. Ther., 321 (3): 1069-74. [PMID:17360702]

15. Solt K, Stevens RJ, Davies PA, Raines DE. (2005) General anesthetic-induced channel gating enhancement of 5-hydroxytryptamine type 3 receptors depends on receptor subunit composition. J. Pharmacol. Exp. Ther., 315 (2): 771-6. [PMID:16081679]

16. Thompson AJ, Jarvis GE, Duke RK, Johnston GA, Lummis SC. (2011) Ginkgolide B and bilobalide block the pore of the 5-HT(3) receptor at a location that overlaps the picrotoxin binding site. Neuropharmacology, 60 (2-3): 488-95. [PMID:21059362]

17. Walstab J, Combrink S, Brüss M, Göthert M, Niesler B, Bönisch H. (2007) Aequorin luminescence-based assay for 5-hydroxytryptamine (serotonin) type 3 receptor characterization. Anal. Biochem., 368 (2): 185-92. [PMID:17617370]

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