5-HT<sub>3</sub>AB | 5-HT<sub>3</sub> receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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5-HT3AB

Target not currently curated in GtoImmuPdb

Target id: 378

Nomenclature: 5-HT3AB

Family: 5-HT3 receptors

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

Quaternary Structure: Subunits
5-HT3A
5-HT3B
Previous and Unofficial Names
5-HT3A/B
Functional Characteristics
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
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
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 Hs Agonist 9.0 pKi 1
pKi 9.0 [1]
meta-chlorphenylbiguanide Hs Agonist 7.0 pKi 1
pKi 7.0 [1]
5-hydroxytryptamine Hs Agonist 6.0 pKi 1
pKi 6.0 [1]
1-phenylbiguanide Hs Agonist 4.9 pKi 1
pKi 4.9 [1]
meta-chlorphenylbiguanide Hs Agonist 5.7 pEC50 5
pEC50 5.7 [5]
5-hydroxytryptamine Hs Agonist 4.8 – 5.8 pEC50 2,5-6,14
pEC50 4.8 – 5.8 [2,5-6,14]
2-methyl-5-HT 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 Hs Antagonist 8.8 pKd 1
pKd 8.8 [1]
(S)-zacopride Hs Antagonist 8.8 pKi 1
pKi 8.8 [1]
azasetron Hs Antagonist 8.4 pKi 1
pKi 8.4 [1]
ondansetron Hs Antagonist 7.8 pKi 1
pKi 7.8 [1]
(R)-zacopride Hs Antagonist 7.7 pKi 1
pKi 7.7 [1]
metoclopramide Hs Antagonist 5.7 pKi 1
pKi 5.7 [1]
cocaine Hs Antagonist 4.8 pKi 1
pKi 4.8 [1]
tubocurarine 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 Hs - no 4.2 pIC50 - no 15
pIC50 4.2 (IC50 6.3x10-5 M) [15]
Not voltage dependent
picrotoxin Mm - yes 2.9 pIC50 - no 3-4
pIC50 2.9 [3-4]
Not voltage dependent
bilobalide Hs - no 2.5 pIC50 - no 15
pIC50 2.5 (IC50 3.1x10-3 M) [15]
Not voltage dependent
ginkgolide B Hs - no 2.4 pIC50 - no 15
pIC50 2.4 (IC50 3.9x10-3 M) [15]
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 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 [13-14].
Functional Assays
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:  16
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. 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]

14. 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]

15. 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]

16. 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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