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α1D-adrenoceptor

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Target id: 24

Nomenclature: α1D-adrenoceptor

Family: Adrenoceptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 572 20p13 ADRA1D adrenoceptor alpha 1D 8
Mouse 7 562 2 63.5 cM Adra1d adrenergic receptor, alpha 1d 3
Rat 7 561 3q36 Adra1d adrenoceptor alpha 1D 63
Previous and Unofficial Names Click here for help
ADRA1 | Adra-1 | ADRA1A | ADRA1R | Adrd1 | adrenergic receptor delta1 | α1A-adrenoceptor | α1A/D | α1a/d-adrenoceptor | alpha 1D-adrenoceptor | alpha 1D-adrenoreceptor | alpha1D-AR | Gpcr8
Database Links Click here for help
Specialist databases
GPCRdb ada1d_human (Hs), ada1d_mouse (Mm), ada1d_rat (Rn)
Other databases
Alphafold P25100 (Hs), P97714 (Mm), P23944 (Rn)
ChEMBL Target CHEMBL223 (Hs), CHEMBL2130 (Mm), CHEMBL326 (Rn)
DrugBank Target P25100 (Hs), P25100 (Hs), P25100 (Hs)
Ensembl Gene ENSG00000171873 (Hs), ENSMUSG00000027335 (Mm), ENSRNOG00000021256 (Rn)
Entrez Gene 146 (Hs), 11550 (Mm), 29413 (Rn)
Human Protein Atlas ENSG00000171873 (Hs)
KEGG Gene hsa:146 (Hs), mmu:11550 (Mm), rno:29413 (Rn)
OMIM 104219 (Hs)
Pharos P25100 (Hs)
RefSeq Nucleotide NM_000678 (Hs), NM_013460 (Mm), NM_024483 (Rn)
RefSeq Protein NP_000669 (Hs), NP_038488 (Mm), NP_077809 (Rn)
UniProtKB P25100 (Hs), P97714 (Mm), P23944 (Rn)
Wikipedia ADRA1D (Hs)
Natural/Endogenous Ligands Click here for help
(-)-adrenaline
(-)-noradrenaline

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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
cirazoline Small molecule or natural product Rn Full agonist 6.9 pKi 73
⤷ pKi 6.9 [73]
clonidine Small molecule or natural product Approved drug Ligand has a PDB structure Rn Full agonist 6.9 pKi 73
⤷ pKi 6.9 [73]
St 587 Small molecule or natural product Rn Agonist 6.5 pKi 73
⤷ pKi 6.5 [73]
(-)-noradrenaline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 5.5 – 7.4 pKi 45,86,98
⤷ pKi 5.5 – 7.4 [45,86,98]
(-)-adrenaline Small molecule or natural product Approved drug Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Rn Full agonist 6.3 pKi 73
⤷ pKi 6.3 [73]
(-)-noradrenaline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Rn Full agonist 6.3 pKi 73
⤷ pKi 6.3 [73]
(-)-adrenaline Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Full agonist 5.3 – 7.2 pKi 45,86,98
⤷ pKi 5.3 – 7.2 [45,86,98]
oxymetazoline Small molecule or natural product Approved drug Ligand has a PDB structure Rn Partial agonist 6.2 pKi 73
⤷ pKi 6.2 [73]
SKF 89748 Small molecule or natural product Rn Full agonist 6.1 pKi 73
⤷ pKi 6.1 [73]
6-fluoro-noradrenaline Small molecule or natural product Rn Full agonist 6.0 pKi 73
⤷ pKi 6.0 [73]
xylometazoline Small molecule or natural product Approved drug Rn Agonist 6.0 pKi 73
⤷ pKi 6.0 [73]
(+)-adrenaline Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 6.0 pKi 98
⤷ pKi 6.0 [98]
phenylephrine Small molecule or natural product Approved drug Rn Full agonist 5.9 pKi 73
⤷ pKi 5.9 [73]
oxymetazoline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 5.3 – 6.4 pKi 81,86,98
⤷ pKi 5.3 – 6.4 [81,86,98]
corbadrine Small molecule or natural product Approved drug Rn Full agonist 5.6 pKi 73
⤷ pKi 5.6 [73]
clonidine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 5.6 pKi 86
⤷ pKi 5.6 [86]
indanidine Small molecule or natural product Rn Full agonist 5.5 pKi 73
⤷ pKi 5.5 [73]
cirazoline Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.5 pKi 86
⤷ pKi 5.5 [86]
NS-49 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 5.4 pKi 81
⤷ pKi 5.4 [81]
phenylephrine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Full agonist 4.7 pKi 86
⤷ pKi 4.7 [86]
methoxamine Small molecule or natural product Approved drug Rn Full agonist 4.5 pKi 73
⤷ pKi 4.5 [73]
methoxamine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Full agonist 3.8 – 4.9 pKi 86,98
⤷ pKi 3.8 – 4.9 [86,98]
amidephrine Small molecule or natural product Rn Full agonist 4.2 pKi 73
⤷ pKi 4.2 [73]
(-)-adrenaline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Full agonist 6.7 – 7.7 pEC50 86
⤷ pEC50 6.7 – 7.7 [86]
(-)-noradrenaline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 6.6 – 7.8 pEC50 86
⤷ pEC50 6.6 – 7.8 [86]
phenylephrine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Full agonist 6.2 – 7.2 pEC50 86
⤷ pEC50 6.2 – 7.2 [86]
oxymetazoline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 5.6 – 7.3 pEC50 86
⤷ pEC50 5.6 – 7.3 [86]
cirazoline Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.4 – 6.9 pEC50 86
⤷ pEC50 5.4 – 6.9 [86]
methoxamine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Full agonist 5.1 – 5.4 pEC50 86
⤷ pEC50 5.1 – 5.4 [86]
View species-specific agonist tables
Agonist Comments
Non catecholamine agonists, such as methoxamine and amidephrine, have both low affinity and low intrinsic activity at the α1D- adrenoceptor [73]. There are no selective agonists currently available for α1D-AR.
As the endogenous ligand, (-)-adrenaline has intrinsic activity across the adrenoceptor family, but α1D and α2A subtypes have been identified as primary drug targets as the agonist has highest affinity at these isoforms. A range of pEC50 values are given to reflect findings in different studies and across different signalling assays. Potency of agonists is generally higher for intracellular Ca2+ release than for ERK1/2 phosphorylation. In contrast to α1A- and α1B-AR, no agonists act at α1D-AR to cause cAMP generation [86]. In some cases higher potency for ERK1/2 phosphorylation can reflect off target effects of agonists such as oxymetazoline that also activates 5-HT1B receptors endogenously expressed in CHO cells [19].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
olanzapine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 6.4 pA2 80
⤷ pA2 6.4 [80]
Description: Measured as antagonism of phenylephrine-induced contraction of endothelium-denuded rat aorta.
[125I]HEAT (BE2254) Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.5 – 9.9 pKd 95,98
⤷ pKd 9.5 – 9.9 [95,98]
HEAT (BE2254) Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.5 pKd 98
⤷ pKd 9.5 [98]
RX18 Small molecule or natural product Hs Antagonist 10.3 pKi 90
⤷ pKi 10.3 [90]
A-123189 Small molecule or natural product Click here for species-specific activity table Rn Antagonist 9.8 pKi 10
⤷ pKi 9.8 [10]
tamsulosin 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 9.2 – 10.2 pKi 27,87,98,112
⤷ pKi 9.2 – 10.2 [27,87,98,112]
A-119637 Small molecule or natural product Click here for species-specific activity table Rn Antagonist 9.7 pKi 10
⤷ pKi 9.7 [10]
prazosin 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 Inverse agonist 9.1 – 10.2 pKi 27,87,98,112
⤷ pKi 9.1 – 10.2 [27,87,98,112]
A-119637 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.6 pKi 10
⤷ pKi 9.6 [10]
A-123189 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.5 pKi 10
⤷ pKi 9.5 [10]
(S)-41 Small molecule or natural product Hs Antagonist 9.5 pKi 93
⤷ pKi 9.5 [93]
NAN 190 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.2 pKi 113
⤷ pKi 9.2 [113]
(+)-cyclazosin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inverse agonist 8.5 – 9.9 pKi 32,87
⤷ pKi 8.5 – 9.9 [32,87]
WB 4101 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.6 – 9.6 pKi 27,87,98
⤷ pKi 8.6 – 9.6 [27,87,98]
BMY-7378 Small molecule or natural product Click here for species-specific activity table Rn Antagonist 9.0 pKi 10
⤷ pKi 9.0 [10]
BMY-7378 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.6 – 9.1 pKi 10,87,113
⤷ pKi 8.6 – 9.1 [10,87,113]
doxazosin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.3 – 9.1 pKi 39,87
⤷ pKi 8.3 – 9.1 (Ki 8.13x10-10 M) [39,87]
[3H]prazosin Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Antagonist 8.7 pKi 87
⤷ pKi 8.7 [87]
dapiprazole Small molecule or natural product Approved drug Primary target of this compound Hs Antagonist 8.4 pKi 7,87
⤷ pKi 8.4 (Ki 4.09x10-9 M) [7,87]
phenoxybenzamine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.4 pKi 87
⤷ pKi 8.4 non-competitive antagonist [87]
terazosin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.7 – 9.1 pKi 69,87
⤷ pKi 7.7 – 9.1 (Ki 8.5x10-10 M) [69,87]
spiperone Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.1 pKi 113
⤷ pKi 8.1 [113]
alfuzosin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.7 – 8.4 pKi 41,87
⤷ pKi 7.7 – 8.4 [41,87]
spiroxatrine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.9 pKi 87,113
⤷ pKi 7.9 [87,113]
ketanserin Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.8 pKi 113
⤷ pKi 7.8 [113]
ritanserin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.8 pKi 113
⤷ pKi 7.8 [113]
silodosin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 6.9 – 8.7 pKi 87,98
⤷ pKi 6.9 – 8.7 [87,98]
upidosin Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.8 pKi 27
⤷ pKi 7.8 [27]
RS-100329 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.6 – 7.9 pKi 87,112
⤷ pKi 7.6 – 7.9 [87,112]
clozapine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.7 pKi 113
⤷ pKi 7.7 [113]
KMUP-1 Small molecule or natural product Click here for species-specific activity table Rn Antagonist 7.7 pKi 61
⤷ pKi 7.7 [61]
(+)-cyclazosin Small molecule or natural product Ligand has a PDB structure Rn Inverse agonist 7.6 pKi 32
⤷ pKi 7.6 [32]
mianserin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.5 pKi 113
⤷ pKi 7.5 [113]
phentolamine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inverse agonist 6.8 – 8.2 pKi 87,98
⤷ pKi 6.8 – 8.2 [87,98]
risperidone Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.4 pKi 113
⤷ pKi 7.4 [113]
dibenamine Small molecule or natural product Hs Antagonist 7.4 pKi 87
⤷ pKi 7.4 non-competitive antagonist [87]
RS-17053 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.8 – 7.8 pKi 27,87
⤷ pKi 6.8 – 7.8 [27,87]
Ro-70-0004 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.2 pKi 112
⤷ pKi 7.2 [112]
SKF 105854 Small molecule or natural product Hs Antagonist 7.1 pKi 42
⤷ pKi 7.1 [42]
cyproheptadine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 6.9 pKi 113
⤷ pKi 6.9 [113]
5-methylurapidil Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.6 – 8.0 pKi 27,87,98,113
⤷ pKi 5.6 – 8.0 [27,87,98,113]
S(+)-niguldipine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.9 – 7.4 pKi 27,87,98
⤷ pKi 5.9 – 7.4 [27,87,98]
indoramin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 6.3 – 6.7 pKi 27,87
⤷ pKi 6.3 – 6.7 [27,87]
labetalol Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 6.1 – 6.6 pKi 7,87
⤷ pKi 6.1 – 6.6 [7,87]
SNAP5089 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.7 pKi 87
⤷ pKi 5.7 [87]
RX18 Small molecule or natural product Rn Antagonist 9.1 pEC50 90
⤷ pEC50 9.1 [90]
Description: Antagonist potency determined in isolated rat thoracic aorta
View species-specific antagonist tables
Antagonist Comments
Although cyclazosin does not show selectivity in radioligand binding assays with recombinant α1-ARs, functional selectivity for the α1D-AR is observed in functional assays using isolated tissue measuring affinity for native α1- subtypes [72]. SNAP5089 is >1000-fold and RS-100329 and Ro-70-0004 are both 50-fold selective for α1A-ARs over the α1B- and α1D-AR subtypes [87,112]. BMY-7378 is the only α1D-AR selective antagonist currently available [87] and has some weak partial agonist actions at the α1A, α1B and 5-HT1A receptor [34,86]. Differentiation between neutral antagonists and inverse agonists at the α1D-AR has not been studied extensively. Prazosin, cyclazosin, doxazosin and terazosin are approved drugs that have similar affinity for all α1-AR subtypes. Phenoxybenzamine is an irreversible α1A-AR antagonist used to block the pressor effects of catecholamines prior to surgery for phaeochromocytoma. Labetalol is predominantly a β-AR antagonist but also has some α-AR blocking properties and is considered safe for use in pregnancy to treat eclampsia and pre-eclampsia. It also behaves as a partial agonist in some systems.
Allosteric Modulator Comments
Lorazepam and midazolam have been shown to increase the maximum response to phenylephrine in cells expressing the human α1D-AR [111].
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
Calcium channel
Other - See Comments
Comments:  The α1D-adrenoceptor is coupled to calcium release and inositol phosphate production less efficiently than either the α1A- or α1B-adrenoceptor.
References:  35,71
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Phospholipase D stimulation
Other - See Comments
Comments:  α1-ARs (all subtypes) can also activate protein Kinase C and mitogen activated protein kinases. Some agonists acting at the α1D-AR can weakly activate adenylate cyclase in the presence of forskolin. α1D-AR couples to adenylate cyclase much less efficiently than either the α1A- or α1B-AR and agonists generally have no effect.
References:  35,71,87
Tissue Distribution Click here for help
Epicardial coronary arteries, prefrontal cortex, hippocampus, bladder.
Species:  Human
Technique:  RT-PCR.
References:  52,99-101
α1D- adrenoceptor message and protein is predominant in human bladder.
Species:  Human
Technique:  RNase protection assay, RT-PCR.
References:  67
The α1D-adrenoceptor was the predominant α1 subtype in the human aorta, but either had the lowest expression of the three subtypes, or was not detectable, in other arteries and veins. However, another report showed high expression of α1D-adrenoceptor in blood vessels of human prostate.
Species:  Human
Technique:  RNAse Protection, immunohistochemistry.
References:  91,109
Lymphocytes.
Species:  Human
Technique:  In situ hybridisation.
References:  105
Prefrontal cortex, reticular thalmic nucleus, hippocampus, cingulate cortex, spinal cord.
Species:  Mouse
Technique:  In situ hybridisation.
References:  40,94
Leydig cells.
Species:  Mouse
Technique:  RT-PCR.
References:  48
Concomitant activation of all α1 subtypes in the nucleus accumbens is required for α1adrenergic inhibition of accumbal dopaminergic activity.
Species:  Rat
Technique:  In vivo microdialysis.
References:  4
Activation of the bladder mechanosensory fibres.
Species:  Rat
Technique:  Single-unit afferent nerve fibre activity (SAA) of primary bladder afferent nerves and their relationship with bladder microcontractions in rats.
References:  2
In the rat brain, highest levels of α1D-adrenoceptor message are found in the olfactory bulb, cerebral cortex, hippocampus, dentate gyrus, reticular thalamic nucleus, motor neurons and the inferior olivary complex. In the thalamus, the α1B and α1D-adrenoceptors have a complimentary distribution.
Species:  Rat
Technique:  In situ hybridisation, RT-PCR.
References:  21,78,97
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Contraction of isolated rat aortic ring and skeletal muscle arteriole.
Species:  Rat
Tissue:  Vasculature.
Response measured:  Contraction.
References:  43,60
Tamsulosin treatment upregulates both α1A- and α1D-AR mRNA.
Species:  Rat
Tissue:  Prostate.
Response measured:  Receptor mRNA expression.
References:  56
Regulation of hippocampal α1D-AR mRNA by corticosterone in adrenalectomized rats. Corticosteroids prevent the adrenalectomized decrease in hippocampal α1D-AR.
Species:  Rat
Tissue:  Brain.
Response measured:  Receptor expression.
References:  21
The α1D-AR is intracellular but still mediates increases in intracellular calcium and reactive oxygen species.
Species:  Human
Tissue:  Aortic smooth muscle, transfected HEK 293 cells.
Response measured:  Measurement of intracellular calcium and reactive oxygen species.
References:  29,54,110
Amino acids Asp176 in the third transmembrane domain (TMD), Glu237 in TMD IV, and Ser258 in TMD V of α1D-AR are involved in binding prazosin and tamsulosin.
Species:  Human
Tissue:  Transfected HEK 293 cells.
Response measured:  Receptor binding.
References:  77
Alteration of α1D-AR density, signal transduction and blood pressure by syntrophins (α-syntrophin increases α1D-AR density; β2-syntrophin increases signaling efficacy of inositol phosphates and ERK).
Species:  Human
Tissue:  Transfected HEK 293 cells.
Response measured:  Receptor density and signalling.
References:  14,64-65
α1D-AR releases ATP, which induces P2X7 receptors to increase [Ca2+](i) but not to stimulate protein secretion. P2X7 receptors in turn activate α1D-AR to increase [Ca2+](i) but not to stimulate protein secretion.
Species:  Rat
Tissue:  Lacrimal gland.
Response measured:  [Ca2+](i).
References:  20
Function and phosphorylation state of α1D-AR is modulated by activation of receptor tyrosine kinases, PKC, insulin, IGF-I and EGF.
Species:  Rat
Tissue:  Transfected Rat-1 fibroblasts.
Response measured:  Phosphorylation and desensitization.
References:  30-31,89
The α1D-AR induces vascular smooth muscle apoptosis via a p53-dependent mechanism.
Species:  Human
Tissue:  Aortic smooth muscle cells.
Response measured:  Apoptosis.
References:  28
α1D-AR promotes trophic effects(pseudocapillary formation, proliferation and migration) in fragments of human mature vessels and is potentiated with hypoxia.
Species:  Human
Tissue:  Endothelial cells.
Response measured:  Cell trophism.
References:  108
α1D-AR stimulates protein secretion and ectodomain shedding of EGF to transactivate the EGF receptor, potentially via ADAM17, which activates p42/p44 MAPK to negatively modulate protein secretion.
Species:  Rat
Tissue:  Lacrimal gland epithelial cells.
Response measured:  Measurement of EGF release and receptor activation.
References:  12,44
Addition of a signal peptide sequence (16 amino acids) to, or N-terminal truncation of the α1D-AR gene increases expression of binding sites but not protein.
Species:  Human
Tissue:  Transfected neuro2A and COS-1 cells
Response measured:  [3H]-prazosin binding to α1D-AR.
References:  83,85
Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by α1D- and α1B-AR.
Species:  Human
Tissue:  Transfected HEK 293 cells.
Response measured:  Measurement of intracellular calcium.
References:  58
In a renal artery stenosis model, GRK2 gene knockout or GRKct peptide treated mice enhance α1D-AR vasoconstriction.
Species:  Mouse
Tissue:  Kidney.
Response measured:  Vasoconstriction.
References:  16
Cell surface expression of α1D-AR is controlled by heterodimerization with α1B-or β2-ARs; Angiotensin I receptor hetrodimerizes with α1D-AR in preeclamptic rats.
Species:  Human
Tissue:  Transfected HEK 293 cells, rat aorta.
Response measured:  Receptor dimerization.
References:  14,33,36-37,106
Methylation-dependent disruption of Sp1 binding in promoter region in a cell-specific manner results in repression of basal α1D-AR expression
Species:  Human
Tissue:  SK-N-MC and DU145 cells.
Response measured:  DNA methylation, receptor expression.
References:  70
Regulation of α1D-AR signal complex signalosome.
Species:  Human
Tissue:  Transfected HEK 293 cells.
Response measured:  Coimmunoprecipitation and blot overlay assays.
References:  66
The selectivity of α-AR agonists for the human α1A, α1B, and α1D-ARs.
Species:  Human
Tissue:  CHO-K1 cell stably expressing α1D-AR.
Response measured:  Whole cell [3H]prazosin binding, intracellular Ca2+ release, ERK1/2 phosphorylation and cAMP accumulation.
References:  86
The affinity and selectivity of α-AR antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D-ARs.
Species:  Human
Tissue:  CHO-K1 cell stably expressing α1D-AR.
Response measured:  Whole cell [3H]prazosin binding.
References:  87
Role of α1D-AR phosphorylation sites in 3rd IC loop and C-terminus in Ca2+ signalling, ERK modulation, plasma membrane localisation and β-arrestin interaction.
Species:  Human
Tissue:  Transfected HEK 293 cells.
Response measured:  Receptor phosphorylation, Ca2+ concentration, ERK1/2 activation, receptor internalisation and interaction with β-arrestin.
References:  9
α1D-ARs are responsible for the greater contractile sensitivity, slower time-course and post-activation contraction to an adrenoceptor-mediated stimulus in conductance vessels.
Species:  Rat
Tissue:  Aorta and tail artery.
Response measured:  Contractile response, inositol phosphate accumulation, ERK1/2 phosphorylation.
References:  26
Scribble binds multiple α1D-AR C-terminal PDZ ligands.
Species:  Human
Tissue:  Transfected HEK 293 cells.
Response measured:  DMR, SNAP GST pulldown, co-IP, biolayer interferometry, x-ray crystallography.
References:  50
N-glycosylation of α1D-AR N-terminal domain is required for correct trafficking, function, and biogenesis.
Species:  Human
Tissue:  Transfected HEK 293 cells.
Response measured:  DMR, sucrose density centrifugation, confocal microscopy, co-localisation analysis.
References:  51
Endogenous N-terminal domain cleavage modulates α1D-AR pharmacodynamics.
Species:  Human
Tissue:  HEK 293, SW480, HEPG2, MCF7, and A375 cells.
Response measured:  DMR, SNAP tagged proteins, immunoblotting, mass spec, PI hydrolysis, radioligand binding, live cell imaging and cell surface localisation.
References:  59
Cross-talk between α1D-AR and TRP-V1 receptors triggers prostate cancer cell proliferation.
Species:  Human
Tissue:  PC3 and DU145 cells.
Response measured:  Western blotting, ECAR, siRNA, qRT-PCR, Ca2+, BrdU, IP3 assays.
References:  76
Cross-talk with β2-ARs enhances ligand affinity properties from endothelial α1D-AR that mediates carotid relaxation.
Species:  Rat
Tissue:  Carotid artery.
Response measured:  Relaxation and contraction.
References:  84
α1D-AR transactivates EGFR.
Species:  Human
Tissue:  CHO cells stably expressing α1D-AR and transiently expressing EGFR.
Response measured:  Calcium increases and activation of CaMKII, PI3K, and Src, but not ERK1/2 and Akt.
References:  107
Physiological Functions Click here for help
Contraction of mesenteric resistance arteries.
Species:  Rat
Tissue:  Vasculature.
References:  71
α1D-adrenoceptors mediate nerve stimulated contraction of corpus cavernosa.
Species:  Rat
Tissue:  Corpus Cavernosa.
References:  75
Coronary artery vasoconstriction.
Species:  Mouse
Tissue:  Vasculature.
References:  11
Femoral artery vasoconstriction.
Species:  Rat
Tissue:  Vasculature.
References:  47
Locomotor activity in response to environmental stimulation.
Species:  Mouse
Tissue:  Brain.
References:  92
Reflex evoked urethral contraction.
Species:  Rat
Tissue:  Urethra.
References:  17
Endothelium dependent vasodilation of mesenteric vascular bed.
Species:  Rat
Tissue:  Vasculature.
References:  25
Vasopressor nerve responses in the pithed rat, previously identified as α2-ARr mediated, may be α1D-AR mediated.
Species:  Rat
Tissue:  Carotid artery.
References:  23-24
Management of distal ureteral stone by α1D-AR antagonist naftopidil.
Species:  Human
Tissue:  Kidney, ureter, bladder.
References:  115
Control of carotid and mesenteric vasoconstriction by α1D-AR as revealed in α1A/B double knockout mice.
Species:  Mouse
Tissue:  Carotid and mesenteric vasculature.
References:  6,15,68
Role of α1D-AR in the renal vascular response to high-fructose feeding.
Species:  Rat
Tissue:  Kidney.
References:  1
Role of α1A- and α1D-ARs in renal vasoconstriction and haemodynamics in diabetes.
Species:  Rat
Tissue:  Kidney.
References:  5
Role of α1D-AR in choice of α1A-AR antagonist for treatment of prostate hyperplasia.
Species:  Human
Tissue:  Prostate.
References:  55
Impairment of α1D-AR-induced relaxation of rat carotid artery during endothelial dysfunction.
Species:  Rat
Tissue:  Carotid artery.
References:  22
α1D-AR in the urothelium facilitate the micturition reflex and storage.
Species:  Mouse
Tissue:  Bladder.
References:  13,49,96
Role of α1D-AR in contraction of femoral resistance arteries.
Species:  Mouse
Tissue:  Femoral artery.
References:  114
Prostate cancer cell proliferation.
Species:  Human
Tissue:  Prostate cancer PC3 cells.
References:  76
Pathogenesis of hypertension.
Species:  Rat
Tissue:  Blood pressure and cardiac function.
References:  88
Proliferation of pulmonary artery smooth muscle.
Species:  Rat
Tissue:  Pulmonary artery smooth muscle cells.
References:  62
Food intake.
Species:  Rat
Tissue:  Median raphe nucleus.
References:  18
α1D-ARs and high sensitivity slow time-course contraction in conductance arteries; rat and α1D-AR knockout mice.
Species:  Rat
Tissue:  Aorta and tail artery.
References:  26
Physiological Consequences of Altering Gene Expression Click here for help
α1D knockout mice had hypotension, a decreased pressor and decreased coronary vasoconstrictor response to phenylephrine and resistance to salt induced hypertension.
Species:  Mouse
Tissue: 
Technique:  Transgenesis.
References:  11,103-104
α1D knockout mice have delayed tail-flick and hindpaw-licking responses to thermal stimuli.
Species:  Mouse
Tissue: 
Technique:  Gene knockout.
References:  40
α1D-AR knockout mice have lower levels of basal systolic and mean arterial BP, and lower levels of circulating catecholamines than wild-type mice; effects of salt-loading.
Species:  Mouse
Tissue:  Vasculature.
Technique:  Gene knockout.
References:  46,103
α1D-AR has a role in auditory sensory function, attention or working memory rather than reference memory, and the sensorimotor gating deficits induced by the NMDA receptor antagonist. Mice show sensory, attention and memory abnormalities of behavior.
Species:  Mouse
Tissue:  Brain, behavior.
Technique:  Gene knockout.
References:  74
α1D-AR knockout mice lose the slow decay of response in aorta following agonist removal.
Species:  Mouse
Tissue:  Aorta.
Technique:  Gene knockout.
References:  26
Xenobiotics Influencing Gene Expression Click here for help
Peroxynitrite generated through septic shock (bacterial infection) can inhibit maximum binding and signal transduction (intracellular calcium) of the α1A- and α1D-AR. This may be due to modification of these receptor subtypes by peroxynitrite and represents a possible mechanism contributing to systemic hypotension in sepsis.
Species:  Human
Tissue:  CHO cells transfected with the human α1A-, α1B- and α1D-ARs.
Technique:  Ligand binding and measurement of intracellular calcium.
References:  102
Peroxynitrite generated through septic shock (bacterial infection) can inhibit noradrenaline-induced contraction in rat endothelium-denuded aorta strips which contain 1A- and 1D-AR subtypes and represents a possible contributory mechanism underlying systemic hypotension in sepsis.
Species:  Rat
Tissue:  Endothelium-denuded aorta strips.
Technique:  Recording of tension changes in organ bath culture.
References:  102
Erythropoietin reverses sepsis-induced vasoplegia to norepinephrine through preservation of α1D-AR mRNA expression in mouse aorta.
Species:  Mouse
Tissue:  Thoracic aorta.
Technique:  Survival time, contractile response, NO level, iNOS, eNOS, GRK2 and α1D-AR expression (mRNA and protein).
References:  53
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Adra1dtm1Gzt Adra1dtm1Gzt/Adra1dtm1Gzt
involves: 129/Sv * C57BL/6J		 MGI:106673  MP:0001544 abnormal cardiovascular system physiology PMID: 11901185 
Adra1dtm1Jabl Adra1dtm1Jabl/Adra1dtm1Jabl
involves: 129S6/SvEvTac		 MGI:106673  MP:0003313 abnormal locomotor activation PMID: 12874602 
Adra1dtm1Gzt Adra1dtm1Gzt/Adra1dtm1Gzt
involves: 129X1/SvJ * C57BL/6		 MGI:106673  MP:0004142 abnormal muscle tone PMID: 15196805 
Adra1dtm1Gzt Adra1dtm1Gzt/Adra1dtm1Gzt
involves: 129X1/SvJ * C57BL/6		 MGI:106673  MP:0003088 abnormal prepulse inhibition PMID: 15196805 
Adra1dtm1Gzt Adra1dtm1Gzt/Adra1dtm1Gzt
involves: 129X1/SvJ * C57BL/6		 MGI:106673  MP:0008428 abnormal spatial working memory PMID: 15196805 
Adra1dtm1Gzt Adra1dtm1Gzt/Adra1dtm1Gzt
involves: 129X1/SvJ * C57BL/6		 MGI:106673  MP:0001489 decreased startle reflex PMID: 15196805 
Adra1dtm1Gzt Adra1dtm1Gzt/Adra1dtm1Gzt
involves: 129/Sv * C57BL/6J		 MGI:106673  MP:0002843 decreased systemic arterial blood pressure PMID: 11901185 
Adra1dtm1Gzt Adra1dtm1Gzt/Adra1dtm1Gzt
involves: 129/Sv * C57BL/6J		 MGI:106673  MP:0006264 decreased systemic arterial systolic blood pressure PMID: 11901185 
Adra1dtm1Jabl Adra1dtm1Jabl/Adra1dtm1Jabl
involves: 129S6/SvEvTac		 MGI:106673  MP:0002757 decreased vertical activity PMID: 12874602 
Adra1dtm1Gzt Adra1dtm1Gzt/Adra1dtm1Gzt
involves: 129X1/SvJ * C57BL/6		 MGI:106673  MP:0003858 enhanced coordination PMID: 15196805 
Adra1dtm1Gzt Adra1dtm1Gzt/Adra1dtm1Gzt
involves: 129/Sv * C57BL/6J		 MGI:106673  MP:0001596 hypotension PMID: 11901185 
Adra1dtm1Jabl Adra1dtm1Jabl/Adra1dtm1Jabl
involves: 129S6/SvEvTac		 MGI:106673  MP:0009750 impaired behavioral response to addictive substance PMID: 12874602 
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphisms
Species:  Human
Description:  ADRA1D T1848A (P=0.023) and ADRA1D A1905G (P=0.029) SNPs are associated with the improvement of left ventricular fractional shortening by β-blockers in chronic heart failure.
SNP accession:  rs2236554, rs709024
References:  79
Type:  Single nucleotide polymorphisms
Species:  Human
Description:  The side effects of domperidone to treat gastroparesis are associated with SNPs in the α1D-AR promoter region.
SNP accession:  rs6107461, rs6084673, rs6052462, rs4813680
References:  82
General Comments
α1D-AR message and protein is predominant in human bladder [67]. In bladder tissue from normal rats, only 25% of α1-AR mRNA was of the α1D-subtype; however following bladder obstruction, this percentage increased to 75% [38].
When recombinant α1D-ARs are expressed in fibroblast cell lines, most of the expression is intracellular, as opposed to the cell surface expression of the other α1 subtypes [57].

References

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