Superconserved receptors expressed in the brain: Expression, function, motifs and evolution of an orphan receptor family

Elsevier

Available online 26 May 2022, 108217

Pharmacology & TherapeuticsAbstract

GPR27, 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.

Keywords

G protein-coupled receptors

Superconserved receptors expressed in the brain

Orphan GPCR

GPR85

GPR27

GPR173

AbbreviationsβAR

β-Adrenergic receptors

β2AR

β2-Adrenergic receptor

β3AR

β3-Adrenergic receptor

D2

Dopaminergic receptor 2

D4

Dopaminergic receptor 4

EST

Expressed Sequence Tags

FSH

Follicle-Stimulating Hormone

GnRH

Gonadotropin-releasing hormone

GPCR

G protein-coupled receptors

GRK

G protein-coupled receptor kinase

HCC

Hepatocellular carcinoma

5HT1A

Serotonin receptor 1A

IUPHAR

International Union of Basic and Clinical Pharmacology

M2

Musacarinic M2 receptor

MC4R

Melanocortin receptor 4

mPFC

medial Prefrontal Cortex

PSD-95

postsynaptic density protein 95

RXFP

Relaxin family Receptor

SHANK

SH3 And Multiple Ankyrin Repeat Domains

SREB

Super Conserved Receptors Expressed in the Brain

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