Available online 26 May 2022, 108217
AbstractGPR27, GPR85 and GPR173 constitute a small family of G protein-coupled receptors (GPCR) that share the distinctive characteristics of being highly conserved throughout vertebrate evolution and predominantly expressed in the brain. Accordingly, they have been coined as “Superconserved Receptors Expressed in the Brain” (SREB), although their expression profile is more complex than what was originally thought. SREBs have no known validated endogenous ligands and are thus labeled as “orphan” receptors. The investigation of this particular category of uncharacterized receptors holds great promise both in terms of physiology and drug development. In the largest GPCR family, the Rhodopsin-like or Class A, around 100 receptors are considered orphans. Because GPCRs are the most successful source of drug targets, the discovery of a novel function or ligand most likely will lead to significant breakthroughs for the discovery of innovative therapies.
The high level of conservation is one of the characteristic features of the SREBs. We propose herein a detailed analysis of the putative evolutionary origin of this family. We highlight the properties that distinguish SREBs from other rhodopsin-like GPCRs. We present the current evidence for these receptors downstream signaling pathways and functions. We discuss the pharmacological challenge for the identification of natural or synthetic ligands of orphan receptors like SREBs. The different SREB-related scientific questions are presented with a highlight on what should be addressed in the near future, including the confirmation of published evidence and their validation as drug targets. In particular, we discuss in which pathological conditions these receptors may be of great relevance to solve unmet medical needs.
KeywordsG protein-coupled receptors
Superconserved receptors expressed in the brain
Orphan GPCR
GPR85
GPR27
GPR173
AbbreviationsβARβ-Adrenergic receptors
β2ARβ2-Adrenergic receptor
β3ARβ3-Adrenergic receptor
D2Dopaminergic receptor 2
D4Dopaminergic receptor 4
ESTExpressed Sequence Tags
FSHFollicle-Stimulating Hormone
GnRHGonadotropin-releasing hormone
GPCRG protein-coupled receptors
GRKG protein-coupled receptor kinase
HCCHepatocellular carcinoma
5HT1ASerotonin receptor 1A
IUPHARInternational Union of Basic and Clinical Pharmacology
M2Musacarinic M2 receptor
MC4RMelanocortin receptor 4
mPFCmedial Prefrontal Cortex
PSD-95postsynaptic density protein 95
RXFPRelaxin family Receptor
SHANKSH3 And Multiple Ankyrin Repeat Domains
SREBSuper Conserved Receptors Expressed in the Brain
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