ACKR5

Summary

ACKR5 (atypical chemokine receptor 5, HGNC:13708) is a protein-coding gene on chromosome 12q13.3, encoding Atypical chemokine receptor 5 (O15218). Atypical chemokine receptor that regulates chemokine levels and localization through chemokine binding, independently of activating classical ligand-induced signaling pathways such as G-protein activation and Ca(2+) mobilization.

Adrenomedullin is a potent vasodilator peptide that exerts major effects on cardiovascular function. This gene encodes a seven-transmembrane protein that belongs to the family 1 of G-protein coupled receptors. Studies of the rat counterpart suggest that the encoded protein may function as a receptor for adrenomedullin.

Source: NCBI Gene 11318 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 27 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_007264

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13708
Approved symbol	ACKR5
Name	atypical chemokine receptor 5
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	hrhAMR, G10D, AM-R
Ensembl gene	ENSG00000166856
Ensembl biotype	protein_coding
OMIM	605307
Entrez	11318

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000300098, ENST00000556850, ENST00000622922, ENST00000885415, ENST00000956655

RefSeq mRNA: 1 — MANE Select: NM_007264 NM_007264

CCDS: CCDS8927

Canonical transcript exons

ENST00000300098 — 2 exons

Exon	Start	End
ENSE00001107255	56995194	56998447
ENSE00001237992	56994492	56994648

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 89.62.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1068 / max 22.6877, expressed in 34 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126132	0.0572	22
126134	0.0245	10
126135	0.0144	3
126133	0.0106	4

Top tissues by expression

269 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.62	gold quality
spleen	UBERON:0002106	80.68	gold quality
sperm	CL:0000019	77.73	gold quality
male germ cell	CL:0000015	75.45	gold quality
pancreatic ductal cell	CL:0002079	71.47	silver quality
tendon of biceps brachii	UBERON:0008188	71.32	gold quality
triceps brachii	UBERON:0001509	70.44	gold quality
gluteal muscle	UBERON:0002000	68.69	gold quality
left adrenal gland cortex	UBERON:0035825	68.47	gold quality
right adrenal gland cortex	UBERON:0035827	68.25	gold quality
tibialis anterior	UBERON:0001385	68.15	silver quality
left adrenal gland	UBERON:0001234	68.02	gold quality
adrenal cortex	UBERON:0001235	68.02	gold quality
liver	UBERON:0002107	67.94	gold quality
adrenal gland	UBERON:0002369	67.44	gold quality
right adrenal gland	UBERON:0001233	67.21	gold quality
right testis	UBERON:0004534	67.17	gold quality
left testis	UBERON:0004533	66.66	gold quality
buccal mucosa cell	CL:0002336	66.50	gold quality
adrenal tissue	UBERON:0018303	65.64	gold quality
lymph node	UBERON:0000029	64.84	gold quality
right lobe of liver	UBERON:0001114	64.72	gold quality
testis	UBERON:0000473	64.40	gold quality
deltoid	UBERON:0001476	62.90	gold quality
trabecular bone tissue	UBERON:0002483	62.87	gold quality
ileal mucosa	UBERON:0000331	62.80	silver quality
colonic epithelium	UBERON:0000397	61.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	61.35	gold quality
secondary oocyte	CL:0000655	60.99	gold quality
right lobe of thyroid gland	UBERON:0001119	60.51	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting ACKR5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-16-1-3P	98.70	69.23	1538
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-1224-3P	97.24	65.92	851
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-6772-3P	97.04	65.89	784
HSA-MIR-4662A-3P	97.02	67.77	941

Literature-anchored findings (GeneRIF, showing 12)

• Endogenous ADM system plays a potentially important role in the paracrine or autocrine functional control of Conn’s adenomas. (PMID:11712085)
• The cardiovascular response in sepsis: proposed mechanisms of the beneficial effect of adrenomedullin and its binding protein (review). (PMID:11956648)
• The co-expression of Adm and its receptor in perineural fibroblasts and the expression of an Adm receptor in Schwann cells suggest autocrine and/or paracrine modes of action of Adm in peripheral nerves. (PMID:12419522)
• Chondrocyte phenotype cells expressed adrenomedullin and the adrenomedullin receptor, and secreted high concentration of adrenomedullin into the culture medium (PMID:12646214)
• Hybridization in situ showed that ADMR mRNA expression was significantly higher in pulmonary artery walls in patients with chronic obstructive pulmonary disease. (PMID:14720432)
• distribution of adrenomedullin receptor (AM-R )in the villous and extravillous trophoblast cells of the placenta and in chorion and decidua cells of the fetal membranes changed with gestational age but not with labor (PMID:17939601)
• ADMR mediates the stimulatory effects of adrenomedullin on cancer cells and on endothelial and stellate cells within the tumor microenvironment (PMID:19847298)
• Gene expression of adrenomedullin receptor components are differentially regulated in the uterus during the estrous cycle. (PMID:23442365)
• Our data demonstrate that GPR182 is an endothelial subtype-specific marker for human sinusoidal EC of the liver, spleen, lymph node and bone marrow. In addition, we provide evidence for GPR182-dependent downstream signaling via ERK and SRF pathways that may be involved in regulating endothelial subtype-specific sinusoidal differentiation and sinusoidal functions such as permeability. (PMID:29408502)
• GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis. (PMID:33875597)
• GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models. (PMID:35013216)
• This putative G protein-coupled receptor remains an orphan, as the ability to bind and be activated by adrenomedullin has been refuted. A complex of CRLR and RAMP2 or RAMP3 gives a functional adrenomedullin receptor. (PMID:9535752)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpr182	ENSDARG00000036616
mus_musculus	Gpr182	ENSMUSG00000058396
rattus_norvegicus	Gpr182	ENSRNOG00000004311

Paralogs (1): GPER1 (ENSG00000164850)

Protein

Protein identifiers

Atypical chemokine receptor 5 — O15218 (reviewed: O15218)

Alternative names: G-protein coupled receptor 182

All UniProt accessions (3): O15218, A0A0D9SG31, Q7Z4H2

UniProt curated annotations — full annotation on UniProt →

Function. Atypical chemokine receptor that regulates chemokine levels and localization through chemokine binding, independently of activating classical ligand-induced signaling pathways such as G-protein activation and Ca(2+) mobilization. Instead, it mediates chemokine sequestration, transport, or internalization to control their availability. Acts as a scavenger for a broad range of chemokines from CXC, CC and XC chemokine ligand famillies including CXCL9, CXCL10, CXCL12, CXCL13, CXCL11, CXCL14, CCL1, CCL11, CCL19, CCL25, CCL28 and XCL1. Is the only atypical receptor for chemokines CXCL13 and CCL28. Has a strong constitutive association with beta-arrestins, which is essential for intracellular receptor trafficking and chemokine scavenging, and occurs independently of ligand binding. Cooperates with ACKR3 and ACKR4 in regulating serum levels of CXCL12 and CCL19, respectively. Acts as an important modulator of cellular immunity.

Subunit / interactions. Strong constitutive association with beta-arrestins; leading to internalization of ACKR5 and its ligands.

Subcellular location. Cell membrane. Endosome membrane.

Tissue specificity. Highly expressed in heart, skeletal muscle, immune system, adrenal gland and liver.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_009195* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR001350	G10D_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR047143	GPER1-like	Family

Pfam: PF00001

UniProt features (20 total): topological domain 8, transmembrane region 7, glycosylation site 2, chain 1, disulfide bond 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15218-F1	79.73	0.58

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (1): 126–202

Glycosylation sites (2): 28, 37

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 86 (showing top): MODULE_64, MODULE_289, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, GGGNNTTTCC_NFKB_Q6_01, MODULE_123, MODULE_95, GOMF_CYTOKINE_BINDING, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_CHEMOKINE_BINDING, YAGI_AML_SURVIVAL, DODD_NASOPHARYNGEAL_CARCINOMA_DN, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, MODULE_375, MIKKELSEN_MEF_HCP_WITH_H3_UNMETHYLATED, MARTENS_TRETINOIN_RESPONSE_UP

GO Biological Process (3): cell surface receptor signaling pathway (GO:0007166), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (4): transmembrane signaling receptor activity (GO:0004888), G protein-coupled receptor activity (GO:0004930), C-C chemokine binding (GO:0019957), C-X-C chemokine binding (GO:0019958)

GO Cellular Component (3): endosome (GO:0005768), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
chemokine binding	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signaling receptor activity	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
endomembrane system	1
cytoplasmic vesicle	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

430 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACKR5	ADM	P35318	961
ACKR5	ARRB2	P32121	850
ACKR5	ARRB1	P49407	840
ACKR5	CYB5R3	P00387	652
ACKR5	RAMP2	O60895	507
ACKR5	CALCRL	Q16602	507
ACKR5	RAMP3	O60896	476
ACKR5	GNAQ	P50148	472
ACKR5	APLF	Q8IW19	469
ACKR5	LGALS4	P56470	466
ACKR5	PLPP6	Q8IY26	455
ACKR5	RCL1	Q9Y2P8	447
ACKR5	RAMP1	O60894	432
ACKR5	SAG	P10523	431
ACKR5	GIP	P09681	429

IntAct

21 interactions, top by confidence:

A	B	Type	Score
ABHD12	GPR182	psi-mi:“MI:0915”(physical association)	0.550
GPR182	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP1	GPR182	psi-mi:“MI:0915”(physical association)	0.400
GPR182	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
GPR182	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	GPR182	psi-mi:“MI:0915”(physical association)	0.400
GOSR1	GPR182	psi-mi:“MI:0915”(physical association)	0.370
ITGA5	GPR182	psi-mi:“MI:0915”(physical association)	0.370
MPG	GPR182	psi-mi:“MI:0915”(physical association)	0.370
OGFR	GPR182	psi-mi:“MI:0915”(physical association)	0.370
PLPPR3	GPR182	psi-mi:“MI:0915”(physical association)	0.370
TMUB2	GPR182	psi-mi:“MI:0915”(physical association)	0.370
TMEM101	GPR182	psi-mi:“MI:0915”(physical association)	0.370
TMEM30A	GPR182	psi-mi:“MI:0915”(physical association)	0.370
HLA-C	GPR182	psi-mi:“MI:0915”(physical association)	0.370
GPR182	METTL15	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
GPR182	TMEM120B	psi-mi:“MI:0914”(association)	0.350

BioGRID (455): ABHD12 (Two-hybrid), GOSR1 (Two-hybrid), ITGA5 (Two-hybrid), MPG (Two-hybrid), OGFR (Two-hybrid), LPPR3 (Two-hybrid), TMUB2 (Two-hybrid), TMEM101 (Two-hybrid), TMEM30A (Two-hybrid), HLA-C (Two-hybrid), TIMELESS (Affinity Capture-MS), TSC2 (Affinity Capture-MS), TMEM11 (Affinity Capture-MS), UBE3B (Affinity Capture-MS), ELOVL4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IM31, A0A0R4IP11, E9QJ73, F8VQN3, O00270, O00421, O15218, O35457, O97663, P31392, P32302, P34997, P43142, P49685, Q04683, Q0II78, Q0VDU3, Q149R9, Q16570, Q3ZC80, Q67ES2, Q6XKD3, Q75ZH0, Q7TMA4, Q7TQA9, Q7TQP4, Q7TSN5, Q7TSN6, Q863H8, Q8BZR0, Q8TDV2, Q95LF2, Q95LF3, Q95LF4, Q95LF5, Q95LF7, Q95LF9, Q95LG5, Q96CH1, Q96G91

Diamond homologs: A6QNL7, B0F9W3, B3G515, F1MV99, F7EQ49, O08858, O08878, O09047, O15218, O35210, O55197, O70526, O77590, O88680, P21109, P25023, P25024, P25095, P25104, P29089, P29754, P29755, P30411, P30555, P30556, P30937, P30938, P31391, P32299, P32303, P34976, P35343, P35346, P35351, P35370, P35373, P35374, P35377, P35411, P41146

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

27 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	21
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2498574	GRCh37/hg19 12q13.3-14.1(chr12:57064059-59314016)x1	Likely pathogenic

SpliceAI

503 predictions. Top by Δscore:

Variant	Effect	Δscore
12:56994646:CAGGT:C	donor_loss	1.0000
12:56994649:G:GA	donor_loss	1.0000
12:56994649:G:GG	donor_gain	1.0000
12:56994650:T:A	donor_loss	1.0000
12:56994543:G:T	donor_gain	0.9900
12:56994644:CTCAG:C	donor_gain	0.9900
12:56995193:GGC:G	acceptor_gain	0.9900
12:56995193:GGCGT:G	acceptor_gain	0.9900
12:56995086:AGCCC:A	acceptor_gain	0.9800
12:56997072:G:GT	donor_gain	0.9800
12:56994645:TCAG:T	donor_gain	0.9700
12:56995188:CAATA:C	acceptor_loss	0.9700
12:56995190:ATAG:A	acceptor_loss	0.9700
12:56995191:TA:T	acceptor_loss	0.9700
12:56995192:AGG:A	acceptor_loss	0.9700
12:56997073:A:T	donor_gain	0.9700
12:56994646:CAG:C	donor_gain	0.9600
12:56994647:AG:A	donor_gain	0.9600
12:56994648:GG:G	donor_gain	0.9600
12:56995085:TAGCC:T	acceptor_gain	0.9600
12:56995192:A:AG	acceptor_gain	0.9600
12:56995193:G:GG	acceptor_gain	0.9600
12:56997044:G:GT	donor_gain	0.9600
12:56997045:A:T	donor_gain	0.9500
12:56997202:G:GT	donor_gain	0.9400
12:56997203:A:T	donor_gain	0.9300
12:56997221:G:GT	donor_gain	0.9100
12:56996964:A:AG	donor_gain	0.9000
12:56997081:C:G	donor_gain	0.9000
12:56996964:A:G	donor_gain	0.8900

AlphaMissense

2627 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56995624:A:C	S139R	0.986
12:56995626:C:A	S139R	0.986
12:56995626:C:G	S139R	0.986
12:56995651:A:C	S148R	0.981
12:56995653:T:A	S148R	0.981
12:56995653:T:G	S148R	0.981
12:56995627:A:C	S140R	0.974
12:56995629:C:A	S140R	0.974
12:56995629:C:G	S140R	0.974
12:56995888:T:C	F227L	0.973
12:56995890:C:A	F227L	0.973
12:56995890:C:G	F227L	0.973
12:56995741:T:A	W178R	0.972
12:56995741:T:C	W178R	0.972
12:56995566:G:C	W119C	0.970
12:56995566:G:T	W119C	0.970
12:56996008:T:C	F267L	0.963
12:56996010:T:A	F267L	0.963
12:56996010:T:G	F267L	0.963
12:56995617:C:A	N136K	0.961
12:56995617:C:G	N136K	0.961
12:56995564:T:A	W119R	0.957
12:56995564:T:C	W119R	0.957
12:56995813:T:A	C202S	0.955
12:56995814:G:C	C202S	0.955
12:56995585:T:A	C126S	0.952
12:56995586:G:C	C126S	0.952
12:56995408:G:A	G67R	0.951
12:56995408:G:C	G67R	0.951
12:56995813:T:C	C202R	0.948

dbSNP variants (sampled 300 via entrez): RS1000901224 (12:56997414 G>A), RS1001271160 (12:56997754 T>C), RS1001362700 (12:56997326 C>T), RS1001393785 (12:56997091 T>C), RS1002563611 (12:56999040 G>A), RS1002699514 (12:56998817 G>C), RS1002924649 (12:56993159 AC>A), RS1004010513 (12:56996515 A>C,T), RS1005461105 (12:56998037 A>T), RS1005807657 (12:56995735 G>A,C), RS1006051094 (12:56996838 T>C), RS1006130111 (12:56995618 A>C,G), RS1007065643 (12:56993028 T>TGAA), RS1007366008 (12:56994051 G>A), RS1007402799 (12:56994318 G>A)

Disease associations

OMIM: gene MIM:605307 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST006288_14	Heel bone mineral density	1.000000e-11
GCST006288_198	Heel bone mineral density	4.000000e-06
GCST006288_390	Heel bone mineral density	9.000000e-07
GCST007563_7	Allergic disease (asthma, hay fever or eczema)	1.000000e-09
GCST007564_27	Asthma or allergic disease (pleiotropy)	8.000000e-13
GCST008916_110	Asthma	1.000000e-27
GCST008916_18	Asthma	8.000000e-18
GCST008916_2	Asthma	2.000000e-08
GCST010002_217	Refractive error	6.000000e-174

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4356 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Chemokine receptors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
adrenomedullin	Partial agonist	8.15	pEC50

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases expression, decreases reaction	1
VULM 1457	decreases reaction, increases expression, decreases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
Acetaminophen	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Catechin	affects cotreatment, decreases expression	1
Oxygen	decreases reaction, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Gold Compounds	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4883435	Binding	PRESTO-Tango GPCRome screening (GPR182)	Data for DCP probe UCSF924

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_KX50	PathHunter CHO-K1 GPR182 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.