Do orphan G Protein Coupled Receptors self stimulate?

Self-stimulation is frowned on in the Bible — Genesis 38:8-10, but one important G Protein Coupled Receptor (GPCR) may actually do it.  At least 1/3 of the drugs in clinical use manipulate GPCRs, and we have lots of them (at least 826/20,000 protein coding genes according to PNAS 115 p. 12733 ’18).  However only 360 or so are not involved in smell, and in one third of them  we have no idea what the natural ligand for them actually is (Cell vol. 177 p. 1933 ’19).  These are the orphan GPCRs, and they make a juicy target for drug discovery (if only  we knew what they did)

One orphan GPCR goes by the name of GPR52. It is found on neurons carrying the D2 dopamine receptor.  GPR52 binds to G(s) family of G proteins stimulating the production of CAMP (which would antagonize dopamine signaling), enough to stimulate (if not self-stimulate) any neuropharmacologist.

Which brings us to the peculiar behavior of GPR52 as shown by Nature vol. 579 pp. 142 – 147 ’20.  The second extracellular loop (ECL2) folds into what would normally be the binding site for an exogenous ligand (the orthosteric site).  Well, it could be protecting the site from inappropriate ligands.  But it isn’t, as removing or mutating ECL2 decreases the activity of GPR52 (e.g. less CAMP is produced).  Pharmacologists have produced a synthetic GPR52 agonist (called c17).  However it binds to a side pocket, in the 7 transmembrane region of the GCPR.   This is interesting in itself, as no such site is known in any of the other GPCRs studied.

Most GPCRs have some basal (constitutive) activity where they spontaneously couple to their G proteins, but the constitutive activity of GPR52 is quite high, so c17 only slightly increases the rise in CAMP that GPR52 normally produces.

This might be an explanation for other orphan GPCRs — like a hermaphrodite they could be self-fertilizing.

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