Gpr176

G protein-coupled receptor 176 (G protein-coupled receptor AGR9)

Spatial tier: REGION_BIASED · Class: GPCR · Top region: SCH (Suprachiasmatic nucleus) · Positive regions: 45/554

41.5Discovery Score
40.4Targetability Score
CEvidence grade C
What this means: Gpr176: fine CCF profile is region-biased toward SCH (top regions: SCH, MEPO, SBPV, PVa, ARH); this is a discovery lead, not direct proof.

Function in SCH: evidence, prediction, innovation

Gene function
GPR176 is an orphan class A G protein-coupled receptor with high constitutive, agonist-independent activity. Unusually, it couples to the Gz subtype of Gi-family G proteins, tonically lowering cAMP; its own expression is circadian and it is regulated by RGS16.
Region function
The suprachiasmatic nucleus is the master circadian pacemaker: retinorecipient VIP and AVP neurons entrain a cell-autonomous transcriptional clock to the light cycle and impose ~24 h rhythms on sleep, hormones, temperature and behaviour.
Published in this region
direct Direct and definitive. Doi 2016 showed Gpr176 is enriched in the SCN, acts through Gz to constitutively suppress cAMP in pacemaker neurons, and that Gpr176-null mice have a shortened circadian period of behaviour; Goto 2017 and Nakagawa 2020 review how the GPR176-Gz-RGS16 axis sets the pace of the SCN clock across the day.
Predicted function
Prediction: because GPR176 sets the cAMP tone that feeds back onto Per transcription, manipulating it should shift period rather than amplitude. SCN-restricted Gpr176 deletion is predicted to shorten free-running period and weaken the cAMP-dependent phase response to light pulses, while over-expression or a future agonist should lengthen period and dampen daytime firing; the still-unidentified endogenous ligand is the most valuable target, since a GPR176 agonist would be a period-tuning chronotherapeutic.
Innovation
★★☆☆☆ 2/5 This gene-region pair is already established, so the remaining novelty is deorphanisation and cell-type-specific (VIP vs AVP) dissection rather than discovery.
Tools
Gpr176 knockout mice (Doi 2016); no ligand yet, so manipulation is genetic; SCN cell-type access via Vip-Cre, Avp-Cre and Nms-Cre; PER2::LUC reporter mice for ex vivo period measurement.
References

Direct evidence located at the region

Gpr176 Allen ISH at the CCF centroid of SCH

Allen ISH experiment 74511881, section image 74418868 (section 305): the section that contains the CCF centroid of Suprachiasmatic nucleus according to the Allen image-to-atlas alignment (reference_to_image), with a 2 mm window around that point. Left: whole section, red box = window. Middle: ISH signal. Right: Allen's expression-mask view of the same window. open this image in the Allen viewer

Look it up yourself: Allen Mouse Brain ISH for Gpr176Allen reference atlas: SCH (structure 286)ABC Atlas MERFISH viewer(in the ABC Atlas choose dataset MERFISH-C57BL6J-638850-CCF, colour cells by gene "Gpr176" or by parcellation_substructure "SCH")All genes confined to SCH + 3-D brain

Direct spatial evidence

MERFISH REGION LOCATOR
SCH MERFISH region locator
Real single-cell MERFISH coordinates for the SCH (Suprachiasmatic nucleus) section -- our own ground-truth data, showing exactly where this region sits, independent of whether the Allen ISH section below is easy to read.

Regional expression figure

Gpr176 regional expression profile

Predicted WMB × fine-CCF profile; not direct full-transcriptome spatial measurement.

Spatial profile

SCH
4.5
MEPO
3.82
SBPV
3.55
PVa
3.41
ARH
3.31
LC
3.08
AVPV
3.07
PA
3.03
VMH
2.98
VMPO
2.95
DR
2.95
RCH
2.92
DMH
2.87
PVT
2.86
MPN
2.84
CM
2.84
TMv
2.8
PVH
2.74
PERI6a
2.73
PMv
2.71

Evidence and specificity

Evidence status
PREDICTED_FINE
Direct sources
None; predicted localization only
Exclusive threshold
12 positive regions out of 554
Spatial specificity
0.279
Top-region fraction
0.042
Filter status
PASS

Interpretation limits