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5-HT3A

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Target not currently curated in GtoImmuPdb

Target id: 379

Nomenclature: 5-HT3A

Family: 5-HT3 receptors

Contents:

Quaternary Structure: Subunits
5-HT3A
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure of the mouse serotonin 5-HT3 receptor
PDB Id:  4PIR
Resolution:  3.5Å
Species:  Mouse
References:  21
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:  Rb+ = Cs+ = Li+ > Na+ > Ca2+ > Mg2+
References:  41
Species:  Human Mouse
Single channel conductance (pS):  0.3-1.0 0.4-0.6
References:  6,19,41 17,30
Species:  Human
Single channel current rectification:  Inward
References:  6
Species:  Human Mouse
Macroscopic current rectification:  Inward Inward
References:  6,19,41 17,30
Ion Selectivity and Conductance Comments
For the human receptor PCa/PCs = 1.0-1.4 [6,12,36] and PMg/PCs = 0.41-0.61 [6,12]. The fractional calcium flux (Ca2+ Pf) is 4.1% [45].
Natural/Endogenous Ligands Click here for help
Ca2+
5-hydroxytryptamine
Mg2+
Zn2+

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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
[3H]meta-chlorophenylbiguanide Small molecule or natural product Ligand is labelled Ligand is radioactive Mm Partial agonist 9.0 pKd 43
⤷ pKd 9.0 [43]
quipazine Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 9.5 pKi 5
⤷ pKi 9.5 [5]
meta-chlorphenylbiguanide Small molecule or natural product Rn Agonist 9.0 pKi 39,43
⤷ pKi 9.0 [39,43]
CSTI-300 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 8.6 pKi 48
⤷ pKi 8.6 (Ki 2.26x10-9 M) [48]
meta-chlorphenylbiguanide Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.6 – 7.2 pKi 5,24,31,34,39
⤷ pKi 6.6 – 7.2 [5,24,31,34,39]
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 6.5 – 6.9 pKi 5,24,31,34
⤷ pKi 6.5 – 6.9 [5,24,31,34]
2-methyl-5-HT Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.0 – 6.7 pKi 24,31,34,39
⤷ pKi 6.0 – 6.7 [24,31,34,39]
1-phenylbiguanide Small molecule or natural product Mm Partial agonist 6.2 pKi 4
⤷ pKi 6.2 [4]
1-phenylbiguanide Small molecule or natural product Click here for species-specific activity table Hs Agonist 4.7 – 5.6 pKi 4-5,24,34,39
⤷ pKi 4.7 – 5.6 [4-5,24,34,39]
meta-chlorphenylbiguanide Small molecule or natural product Rn Agonist 6.7 – 6.9 pEC50 37,40
⤷ pEC50 6.7 – 6.9 [37,40]
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 5.5 – 6.4 pEC50 3,8,12,15,34,39,50
⤷ pEC50 5.5 – 6.4 [3,8,12,15,34,39,50]
meta-chlorphenylbiguanide Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.4 – 5.8 pEC50 3,12,34,39-40
⤷ pEC50 5.4 – 5.8 (EC50 4x10-6 – 1.6x10-6 M) [3,12,34,39-40]
2-methyl-5-HT Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.5 – 5.6 pEC50 3,12,34,39
⤷ pEC50 5.5 – 5.6 (EC50 3.1x10-6 – 2.5x10-6 M) [3,12,34,39]
SR57227A Small molecule or natural product Rn Agonist 5.4 pEC50 16
⤷ pEC50 5.4 (EC50 3.6x10-6 M) [16]
1-phenylbiguanide Small molecule or natural product Mm Partial agonist 4.5 pEC50 14
⤷ pEC50 4.5 [14]
1-phenylbiguanide Small molecule or natural product Click here for species-specific activity table Hs Agonist 4.1 pEC50 3
⤷ pEC50 4.1 (EC50 8x10-5 M) [3]
View species-specific agonist tables
Agonist Comments
Apparent affinities of agonists are for ligand binding to the recombinant 5-HT3A 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 their affinities/potencies at the latter are in some cases lower. Comments concerning efficacy relate to data obtained from voltage-clamp studies of, where possible, the relevant species orthologues of 5-HT3A receptor expressed in Xenopus laevis oocytes [3,37,50]. Where significant species differences in agonist potency exist, data for rat and mouse orthologues of the receptor are also listed.
Antagonists
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Ligand Sp. Action Value Parameter Reference
[3H]ramosetron Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 9.8 pKd 39
⤷ pKd 9.8 (Kd 1.5x10-10 M) [39]
[3H]GR65630 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 8.6 – 9.3 pKd 23,34
⤷ pKd 8.6 – 9.3 (Kd 2.56x10-9 – 4.8x10-10 M) [23,34]
[3H]granisetron Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 8.9 pKd 5,24
⤷ pKd 8.9 (Kd 1.2x10-9 M) [5,24]
[3H](S)-zacopride Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 8.7 pKd 46
⤷ pKd 8.7 (Kd 2x10-9 M) [46]
[3H]LY278584 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 8.5 pKd 1
⤷ pKd 8.5 (Kd 3.08x10-9 M) [1]
palonosetron Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Antagonist 10.5 pKi 42
⤷ pKi 10.5 (Ki 3.2x10-11 M) [42]
ramosetron Small molecule or natural product Hs Antagonist 10.0 pKi 23
⤷ pKi 10.0 [23]
alosetron Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Antagonist 9.5 pKi 23
⤷ pKi 9.5 (Ki 3.16x10-10 M) [23]
cilansetron Small molecule or natural product Hs Antagonist 9.3 pKi 23
⤷ pKi 9.3 [23]
(S)-zacopride Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.0 pKi 5
⤷ pKi 9.0 (Ki 1x10-9 M) [5]
granisetron Small molecule or natural product Approved drug Primary target of this compound Hs Antagonist ~8.6 – 8.8 pKi 24,39
⤷ pKi ~8.6 – 8.8 (Ki ~2.5x10-9 – 1.5x10-9 M) [24,39]
tropisetron Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.5 – 8.8 pKi 34,39
⤷ pKi 8.5 – 8.8 (Ki 3x10-9 – 1.5x10-9 M) [34,39]
azasetron Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.5 pKi 5
⤷ pKi 8.5 [5]
vortioxetine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Antagonist 8.4 pKi 2
⤷ pKi 8.4 (Ki 3.7x10-9 M) [2]
ricasetron Small molecule or natural product Hs Antagonist 8.2 pKi 5
⤷ pKi 8.2 [5]
ondansetron Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist ~7.8 – 8.3 pKi 5,24,39
⤷ pKi ~7.8 – 8.3 (Ki ~1.5x10-8 – 5x10-9 M) [5,24,39]
AZD0328 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.9 pKi 38
⤷ pKi 7.9 (Ki 1.2x10-8 M) [38]
(R)-zacopride Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.9 pKi 5
⤷ pKi 7.9 [5]
tubocurarine Small molecule or natural product Approved drug Mm Antagonist 6.6 – 7.1 pKi 4,55
⤷ pKi 6.6 – 7.1 [4,55]
metoclopramide Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 6.0 – 6.4 pKi 5,24
⤷ pKi 6.0 – 6.4 (Ki 1.03x10-6 – 3.54x10-7 M) [5,24]
cocaine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 5.1 – 5.4 pKi 5,24
⤷ pKi 5.1 – 5.4 [5,24]
tubocurarine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 4.8 pKi 5,24
⤷ pKi 4.8 [5,24]
View species-specific antagonist tables
Antagonist Comments
Data tabulated are for ligand binding to the recombinant 5-HT3A receptor expressed in mammalian cells. Selectivity refers to the 5-HT3 receptor family: the agents listed no not discriminate between 5-HT3A and 5-HT3AB receptors in radioligand binding assays. In electrophysiological studies, (+)-tubocurarine demonstrates modest selectivity for human 5-HT3A (IC50 = 3 μM) versus human 5-HT3AB (IC50 = 14 – 21 μM) receptors [12]. Where significant species differences in antagonist affinity exist, data for the mouse orthologue of the receptor are also listed.
Channel Blockers
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Ligand Sp. Action Use-dependent Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
TMB-8 Small molecule or natural product Mm - no 5.1 – 5.3 pIC50 - no 35,51
⤷ pIC50 5.1 – 5.3 (IC50 8.4x10-6 – 4.5x10-6 M) [35,51]
Not voltage dependent
picrotoxinin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - no 5.0 pIC50 - no 52
⤷ pIC50 5.0 (IC50 1.1x10-5 M) [52]
Not voltage dependent
TMB-8 Small molecule or natural product Hs - no 4.9 pIC50 - no 51
⤷ pIC50 4.9 (IC50 1.176x10-5 M) [51]
Not voltage dependent
diltiazem Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm - yes 4.2 – 5.3 pIC50 - yes (-60.0) 18,35
⤷ pIC50 4.2 – 5.3 (IC50 7.14x10-5 – 5.5x10-6 M) [18,35]
Voltage dependent: -60.0 mV
diltiazem Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs - no 4.7 pIC50 - no 52
⤷ pIC50 4.7 (IC50 2.1x10-5 M) [52]
Not voltage dependent
picrotoxin Small molecule or natural product Click here for species-specific activity table Mm - yes 4.4 – 4.5 pIC50 - no 9-10
⤷ pIC50 4.4 – 4.5 [9-10]
Not voltage dependent
bilobalide Small molecule or natural product Click here for species-specific activity table Hs - no 3.3 pIC50 - no 52
⤷ pIC50 3.3 (IC50 4.7x10-4 M) [52]
Not voltage dependent
ginkgolide B Small molecule or natural product Click here for species-specific activity table Hs - no 3.1 pIC50 - no 52
⤷ pIC50 3.1 (IC50 7.3x10-4 M) [52]
Not voltage dependent
View species-specific channel blocker tables
Channel Blocker Comments
Although picrotoxin is approximately 27-fold more potent in blocking mouse 5-HT3A versus mouse 5-HT3AB receptors, the degree of discrimination between the equivalent human receptor orthologues is likely to be substantially smaller due to differences in the structure of the TM2 domain [11].
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
ethanol Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Mm Positive - - 3x10-2 - 3x10-1 no 13,22,25,56
⤷ Conc range: 3x10-2 - 3x10-1 M increased channel activation rate, decreased desensitisation rate, decreased deactivation rate. [13,22,25,56]
Not voltage dependent
Mg2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Negative - - 1x10-3 - 1x10-2 no 41
⤷ Conc range: 1x10-3 - 1x10-2 M Decrease in agonist apparent affinity. [41]
Not voltage dependent
Mg2+ Click here for species-specific activity table Ligand is endogenous in the given species Mm Negative - - 1x10-3 - 1x10-2 no 17,44
⤷ Conc range: 1x10-3 - 1x10-2 M decrease in agonist apparent affinity. [17,44]
Not voltage dependent
5-hydroxyindole Small molecule or natural product Ligand has a PDB structure Mm Positive - - 1x10-3 - 1x10-2 no 18,28,33,53
⤷ Conc range: 1x10-3 - 1x10-2 M decreased desensitization rate, decreased deactivation rate, increased apparent affinty of 5-HT. [18,28,33,53]
Not voltage dependent
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 13,22,25,27,56
⤷ Conc range: 2.5x10-4 - 1x10-2 M increased channel activation rate, decreased desensitization rate, decreased deactivation rate. [13,22,25,27,56]
Not voltage dependent
Ca2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Negative - - 1x10-4 - 1x10-2 no 6,41
⤷ Conc range: 1x10-4 - 1x10-2 M Decreased single channel conductance, increased channel activation rate, increased deactivation rate, increased desensitization rate, decrease in agonist apparent affinity. [6,41]
Not voltage dependent
Ca2+ Click here for species-specific activity table Ligand is endogenous in the given species Mm Negative - - 1x10-4 - 1x10-2 no 17,26,44
⤷ Conc range: 1x10-4 - 1x10-2 M Decreased single channel conductance, increased channel activation rate, increased deactivation rate, increased desensitization rate, decrease in agonist apparent affinity. [17,26,44]
Not voltage dependent
Zn2+ Click here for species-specific activity table Ligand is endogenous in the given species Mm Biphasic - - 1x10-6 - 3x10-4 no 17,29
⤷ Conc range: 1x10-6 - 3x10-4 M Positive (1-10μM): increased potency of 5-HT, decreased desensitization rate, reduced effect in the presence of Mg2+ or Ca2+. Negative (30-300μM). [17,29]
Not voltage dependent
View species-specific allosteric modulator tables
Allosteric Modulator Comments
Numerous positive modulators of the 5-HT3A receptor exist, but most also exert effects at other ligand-gated ion channels. Only the most extensively characterised are listed above together with an indication of the range of concentrations over which they modulate submaximal inward currents evoked by 5-HT acting on either mouse of human 5-HT3A receptors expressed in Xenopus laevis oocytes or HEK-293 cells, or 5-HT3 receptors endogenous to clonal cell lines (which are likely to be homomeric 5-HT3A receptors). 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 [49-50].
Functional Assays Click here for help
Measurement of cation current in Xenopus oocytes expressing the 5-HT3A subunit.
Species:  Human
Tissue:  Xenopus laevis oocytes
Response measured:  Cation current under voltage-clamp.
References:  3,39
Measurement of cation current in HEK-293 cells transfected with the 5-HT3A subunit.
Species:  Human
Tissue:  HEK-293 cells
Response measured:  Cation current under voltage-clamp.
References:  6,19,32,41
Measurement of intracellular Ca2+ increase using a FlexStation in HEK-293 cells transfected with the 5-HT3A subunit.
Species:  Mouse
Tissue:  HEK-293 cells
Response measured:  Ca2+-sensitive change in fluorescence.
References:  47
Measurement of [14C]-guanidinium influx in HEK-293 cells transfected with the 5-HT3A subunit.
Species:  Mouse
Tissue:  HEK-293 cells
Response measured:  Intracellular accumulation of ratiotracer.
References:  7
Measurement of intracellular Ca2+ increase using single cell video imaging in HEK-293 cells transfected with the 5-HT3A subunit.
Species:  Mouse
Tissue:  HEK-293 cells
Response measured:  Ca2+-sensitive change in fluorescence.
References:  20
Measurement of Ca2+-induced aequorin luminescence in HEK-293 cells co-transfected with the 5-HT3A subunit and aequorin.
Species:  Human
Tissue:  HEK-293 cells
Response measured:  Ca2+-sensitive change in fluorescence.
References:  54
Indirect measurement of membrane potential using a FlexStation with HEK-293 cells transfected with the 5-HT3A subunit.
Species:  Mouse
Tissue:  HEK-293 cells
Response measured:  Voltage-sensitive change in fluorescence
References:  47

References

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