Nomenclature: α1D-adrenoceptor

Family: Adrenoceptors

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

Contents

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 572 20p13 ADRA1D adrenoceptor alpha 1D 7
Mouse 7 562 2 F1 Adra1d adrenergic receptor, alpha 1d 2
Rat 7 561 3q36 Adra1d adrenoceptor alpha 1D 50
Previous and Unofficial Names
α1A-adrenoceptor
adrenergic receptor
α1a/d-adrenoceptor
α1A/D
α1a/d
ADRA1R
ADRA1A
ADRA1
adrenergic, alpha-1D-, receptor
Adrd1
RA42
adrenergic receptor delta1
adrenergic receptor, alpha 1d
adrenergic receptor, delta1
alpha 1D-adrenoceptor
alpha 1D-adrenoreceptor
alpha-1A adrenergic receptor
alpha-1D adrenergic receptor
alpha-1D adrenoceptor
alpha-1D adrenoreceptor
Gpcr8
Adra-1
alpha1D-AR
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligands
(-)-adrenaline
(-)-noradrenaline
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[125I]HEAT Hs Full agonist 9.5 pKd 78
pKd 9.5 [78]
alfuzosin Hs Agonist 8.44 pKi 35
pKi 8.44 (Ki 3.6x10-9 M) [35]
(-)-noradrenaline Hs Full agonist 7.4 pKi 78
pKi 7.4 [78]
(-)-adrenaline Hs Full agonist 7.2 pKi 78
pKi 7.2 [78]
clonidine Rn Full agonist 6.9 pKi 60
pKi 6.9 [60]
cirazoline Rn Full agonist 6.9 pKi 60
pKi 6.9 [60]
St 587 Rn Full agonist 6.5 pKi 60
pKi 6.5 [60]
oxymetazoline Hs Partial agonist 6.4 pKi 67,78
pKi 6.4 [67,78]
(-)-noradrenaline Rn Full agonist 6.3 pKi 60
pKi 6.3 [60]
(-)-adrenaline Rn Full agonist 6.3 pKi 60
pKi 6.3 [60]
oxymetazoline Rn Partial agonist 6.2 pKi 60
pKi 6.2 [60]
SKF 89748 Rn Full agonist 6.1 pKi 60
pKi 6.1 [60]
(+)-adrenaline Hs Full agonist 6.0 pKi 78
pKi 6.0 [78]
xylometazoline Rn Full agonist 6.0 pKi 60
pKi 6.0 [60]
6-fluoro-noradrenaline Rn Full agonist 6.0 pKi 60
pKi 6.0 [60]
phenylephrine Rn Full agonist 5.9 pKi 60
pKi 5.9 [60]
α-methylnoradrenaline Hs Full agonist 5.6 pKi 60
pKi 5.6 [60]
indanidine Rn Full agonist 5.5 pKi 60
pKi 5.5 [60]
NS-49 Hs Partial agonist 5.4 pKi 67
pKi 5.4 [67]
methoxamine Hs Full agonist 4.9 pKi 78
pKi 4.9 [78]
methoxamine Rn Full agonist 4.5 pKi 60
pKi 4.5 [60]
amidephrine Rn Full agonist 4.2 pKi 60
pKi 4.2 [60]
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[60].
Alfuzosin is an approved drug which is an agonist of several α1-adrenoceptors.
As the endogenous ligand, (-)-adrenaline has intrinsic activity across the adrenoceptor family, but we've only tagged α1D and α2A subtypes as primary drug target as the drug has highest affinity at these isoforms.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
olanzapine Rn Antagonist 6.37 pA2 66
pA2 6.37 [66]
Description: Measured as antagonism of phenylephrine-induced contraction of endothelium-denuded rat aorta.
[125I]BE-2254 Hs Antagonist 9.9 pKd 75
pKd 9.9 [75]
tamsulosin Hs Antagonist 9.8 – 10.2 pKi 22,78,91
pKi 9.8 – 10.2 [22,78,91]
prazosin Hs Inverse agonist 9.5 – 10.2 pKi 22,78,91
pKi 9.5 – 10.2 [22,78,91]
A-123189 Rn Antagonist 9.8 pKi 8
pKi 9.8 [8]
A-119637 Rn Antagonist 9.7 pKi 8
pKi 9.7 [8]
A-119637 Hs Antagonist 9.6 pKi 8
pKi 9.6 [8]
WB 4101 Hs Antagonist 9.6 pKi 22,78
pKi 9.6 [22,78]
A-123189 Hs Antagonist 9.5 pKi 8
pKi 9.5 [8]
NAN 190 Hs Antagonist 9.2 pKi 92
pKi 9.2 [92]
doxazosin Hs Antagonist 9.09 pKi 33
pKi 9.09 (Ki 8.13x10-10 M) [33]
terazosin Hs Antagonist 9.07 pKi 56
pKi 9.07 (Ki 8.5x10-10 M) [56]
BMY-7378 Rn Antagonist 9.0 pKi 8
pKi 9.0 [8]
BMY-7378 Hs Antagonist 8.7 – 9.1 pKi 8,92
pKi 8.7 – 9.1 [8,92]
silodosin Hs Antagonist 8.7 pKi 78
pKi 8.7 [78]
(+)-cyclazosin Hs Inverse agonist 8.5 pKi 27
pKi 8.5 [27]
dapiprazole Hs Antagonist 8.39 pKi 5
pKi 8.39 (Ki 4.09x10-9 M) [5]
phentolamine Hs Inverse agonist 8.2 pKi 78
pKi 8.2 [78]
spiperone Hs Antagonist 8.1 pKi 92
pKi 8.1 [92]
RS-100329 Hs Antagonist 7.9 pKi 91
pKi 7.9 [91]
spiroxatrine Hs Antagonist 7.9 pKi 92
pKi 7.9 [92]
Rec 15/2739 Hs Antagonist 7.8 pKi 22
pKi 7.8 [22]
ritanserin Hs Antagonist 7.8 pKi 92
pKi 7.8 [92]
ketanserin Hs Antagonist 7.8 pKi 92
pKi 7.8 [92]
RS-17053 Hs Antagonist 7.8 pKi 22
pKi 7.8 [22]
clozapine Hs Antagonist 7.7 pKi 92
pKi 7.7 [92]
(+)-cyclazosin Rn Inverse agonist 7.6 pKi 27
pKi 7.6 [27]
5-methylurapidil Hs Antagonist 7.1 – 8.0 pKi 22,78,92
pKi 7.1 – 8.0 [22,78,92]
mianserin Hs Antagonist 7.5 pKi 92
pKi 7.5 [92]
S(+)-niguldipine Hs Antagonist 7.4 pKi 22,78
pKi 7.4 [22,78]
risperidone Hs Antagonist 7.4 pKi 92
pKi 7.4 [92]
Ro-70-0004 Hs Antagonist 7.2 pKi 91
pKi 7.2 [91]
SKF 105854 Hs Antagonist 7.1 pKi 36
pKi 7.1 [36]
cyproheptadine Hs Antagonist 6.9 pKi 92
pKi 6.9 [92]
indoramin Hs Antagonist 6.7 pKi 22
pKi 6.7 [22]
labetalol Hs Antagonist 6.59 pKi 6
pKi 6.59 (Ki 2.56x10-7 M) [6]
View species-specific antagonist tables
Antagonist Comments
Although cyclazosin does not show selectivity in radioligand binding assays with recombinant α1-adrenoceptors, functional selectivity for the α1D-adrenoceptor is observed in functional assays using isolated tissue assays measuring affinity for native α1- subtypes [59]. RS-100329 and Ro-70-0004 are both 50-fold selective for α1A-adrenoceptors over the α1B- and α1D-adrenoceptor subtypes [91].
Differentiation between neutral antagonists and inverse agonists at the α1D- adrenoceptor has not been studied extensively.
Doxazosin and dapiprazole are selective for α1-adrenoceptors.
Allosteric Modulator Comments
Lorazepam and midazolam have been shown to increase the maximum response to phenylephrine in cells expressing the human α1D-adrenoceptor[90].
Primary Transduction Mechanisms
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:  29,58
Secondary Transduction Mechanisms
Transducer Effector/Response
Phospholipase D stimulation
Other - See Comments
Comments:  α1-adrenoceptors (all subtypes) can also activate protein Kinase C, mitogen activated protein kinases.
References:  29,58
Tissue Distribution
α1D- adrenoceptor message and protein is predominant in human bladder.
Species:  Human
Technique:  RNase protection assay, RT-PCR.
References:  54
Epicardial coronary arteries, prefrontal cortex, hippocampus, bladder.
Species:  Human
Technique:  RT-PCR.
References:  43,79-81
Lymphocytes.
Species:  Human
Technique:  In situ hybridisation.
References:  85
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:  72,88
Prefrontal cortex, reticular thalmic nucleus, hippocampus, cingulate cortex, spinal cord.
Species:  Mouse
Technique:  In situ hybridisation.
References:  34,74
Leydig cells.
Species:  Mouse
Technique:  RT-PCR.
References:  41
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:  17,64,77
Expression Datasets

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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
Contraction of isolated rat aortic ring and skeletal muscle arteriole.
Species:  Rat
Tissue:  Vasculature.
Response measured:  Contraction.
References:  37,49
Tamsulosin treatment upregulates both α1A- and α1D-AR mRNA.
Species:  Rat
Tissue:  Prostate.
Response measured:  Receptor mRNA expression.
References:  46
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:  10,38
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:  12,51-52
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:  16
Regualtion of α1D-AR signal complex signalosome.
Species:  Human
Tissue:  Transfected HEK 293 cells.
Response measured:  Coimmunoprecipitation and blot overlay assays.
References:  53
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:  25-26,71
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:  14
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:  12,28,30-31,86
The α1D-AR induces vascular smooth muscle apoptosis via a p53-dependent mechanism.
Species:  Human
Tissue:  Aortic smooth muscle cells.
Response measured:  Apoptosis.
References:  23
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:  17
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:  24,44,89
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:  63
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:  57
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:  87
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:  69-70
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:  48
Physiological Functions
Contraction of mesenteric resistance arteries.
Species:  Rat
Tissue:  Vasculature.
References:  58
α1D-adrenoceptors mediate nerve stimulated contraction of corpus cavernosa.
Species:  Rat
Tissue:  Corpus Cavernosa.
References:  62
Coronary artery vasoconstriction.
Species:  Mouse
Tissue:  Vasculature.
References:  9
Femoral artery vasoconstriction.
Species:  Rat
Tissue:  Vasculature.
References:  40
Locomotor activity in response to environmental stimulation.
Species:  Mouse
Tissue:  Brain.
References:  73
Reflex evoked urethral contraction.
Species:  Rat
Tissue:  Urethra.
References:  15
Endothelium dependent vasodilation of mesenteric vascular bed.
Species:  Rat
Tissue:  Vasculature.
References:  21
Vasopressor nerve responses in the pithed rat, previously identified as α2-ARr mediated, may be α1D-AR mediated.
Species:  Rat
Tissue:  Carotid artery.
References:  19-20
Management of distal ureteral stone by α1D-AR antagonist naftopidil.
Species:  Human
Tissue:  Kidney, ureter, bladder.
References:  94
High-fructose feeding reduces renal vascular response that is blocked by α1D-AR antagonist BMY7378.
Species:  Rat
Tissue:  Kidney.
References:  1
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:  4,13,55
α1A- and α1D-ARs are the major functional subtypes of renal vasoconstriction and haemodynamics in streptozotocin-induced diabetic and normal Sprague-Dawley rats.
Species:  Rat
Tissue:  Kidney.
References:  3
Tamsulosin hydrochloride is more effective in patients with dominant expression of the α1A-AR subtype, whereas naftopidil is more effective in those with dominant expression of the α1D-AR subtype.
Species:  Human
Tissue:  Prostate.
References:  45
α1D-AR-induced relaxation of rat carotid artery is impaired during the endothelial dysfunction evoked in the early stages of hyperhomocysteinemia.
Species:  Rat
Tissue:  Carotid artery.
References:  18
Activation of α1D-AR in the urothelium facilitates the micturition reflex and storage.
Species:  Mouse
Tissue:  Bladder.
References:  11,42,76
Evidence for involvement of α1D-AR in contraction of femoral resistance arteries using knockout mice.
Species:  Mouse
Tissue:  Femoral artery.
References:  93
Physiological Consequences of Altering Gene Expression
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:  9,83-84
α1D knockout mice have delayed tail-flick and hindpaw-licking responses to thermal stimuli.
Species:  Mouse
Tissue: 
Technique:  Gene knockout.
References:  34
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:  39,83
α1D-AR plays an important role in the process of auditory sensory function, attention or working memory rather than reference memory, and the sensorimotor gating deficits induced by the NMDA receptor antagonist. These mice show sensory, attention and memory abnormalities of behavior.
Species:  None
Tissue:  Brain, behavior.
Technique:  Gene knockout.
References:  61
Phenotypes, Alleles and Disease Models Mouse data from MGI

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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 
Xenobiotics Influencing Gene Expression
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:  82
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:  82
Biologically Significant Variants
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: 
References:  65
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: 
References:  68
General Comments
α1D- adrenoceptor message and protein is predominant in human bladder [54]. In bladder tissue from normal rats, only 25% of α1- adrenoceptor message was of the α1D- subtype; however following bladder obstruction, this percentage increased to 75% [32].
When recombinant α1D- adrenoceptors are expressed in fibroblast cell lines, most of the expression is intracellular, as opposed to the cell surface expression of the other α1 subtypes [47].

REFERENCES

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10. Chen L, Hodges RR, Funaki C, Zoukhri D, Gaivin RJ, Perez DM, Dartt DA. (2006) Effects of alpha1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells. Am. J. Physiol., Cell Physiol.291 (5): C946-56. [PMID:16760267]

11. Chen Q, Takahashi S, Zhong S, Hosoda C, Zheng HY, Ogushi T, Fujimura T, Ohta N, Tanoue A, Tsujimoto G et al.. (2005) Function of the lower urinary tract in mice lacking alpha1d-adrenoceptor. J. Urol.174 (1): 370-4. [PMID:15947692]

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14. Cohn HI, Harris DM, Pesant S, Pfeiffer M, Zhou RH, Koch WJ, Dorn GW, Eckhart AD. (2008) Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances alpha1D-adrenergic receptor constriction. Am. J. Physiol. Heart Circ. Physiol.295 (4): H1695-704. [PMID:18723764]

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