Discovery of endogenous inverse agonists for G protein-coupled receptor 6

Abstract

The orphan G protein-coupled receptor 6 (GPR6) is highly expressed in the striatum and1 has been linked to multiple striatal pathologies. The identification of endogenous ligands and their mechanisms of action at GPR6 will help to elucidate the physiological and pathological roles of the receptor. In the current study, we tested the concentration-dependent effects of a variety of endocannabinoid-like N-acylamides on GPR6 signaling. Here, we demonstrate for the first time that N-arachidonoyl dopamine, N-docosahexaenoyl dopamine, N-oleoyl dopamine and Npalmitoyl dopamine exert inverse agonism at GPR6. This effect was concentration-dependent, with potencies in the micromolar range, and functionally selective for β-arrestin2 recruitment. Structure-activity relationship studies demonstrate that both the N-acyl side chain and the dopamine head group are important for these ligands to act on GPR6. Our discovery of these Nacyl dopamines as endogenous inverse agonists for GPR6 moves us one step further in understanding the roles GPR6 play in neurodegenerative and neuropsychiatric disorders related to striatal dysfunction.

Transcriptome Profiling of Dysregulated GPCRs Reveals Overlapping Patterns across Psychiatric Disorders and Age-Disease Interactions

“…The GPCR genes that showed the highest changes in MDD, however, were GPR6 (log2FC > 0.2) and GPR34, P2RY13, and LPAR6 (log2(FC) < −0.2). While there are no studies on the role of GPR6 in MDD, the selective localization of this receptor in the straiatum [ 92 ] and the discovery of endogenous inverse agonists of GPR6 that are dopamine derivatives ( N -arachidonoyl dopamine, N -docosahexaenoyl dopamine, N -oleoyl dopamine, and N -palmitoyl dopamine) [ 93 ] suggest that GPR6 might be a possible therapeutic target for MDD. Interestingly, GPR34, which is activated by lysophosphatidylserine, LPAR6 (lysophosphatidic acid receptor 6), which is also activated by purines (P2RY5), and P2RY13 (Purinergic Receptor P2Y13) are primarily expressed in the microglia and regulate the function and morphology of microglia during neuroinflammation [ 94 , 95 , 96 , 97 , 98 , 99 , 100 ].…”

Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders

“…Altogether the GPCRs are on top as a drug target, and hence they are one the most considerable research subjects for the discovery of novel drugs. Approximately 800 GPCRs for endogenous ligands have been reported in humans and mice [ 14 ]. Identification of these receptors is based on the DNA sequence, not on their ligands, and therefore more than 140 GPCRs, which are without known ligands, are designated as orphan GPCRs or unclassified GPCRs [ 15 ].…”

Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders

“…We have mainly used IRL-1620 (INN-sovateltide) as the agonist of ETBR in our research because of its high selectivity. Sovateltide is a synthetic analog of ET-1 and is also known as PMZ-1620 or SPI-1620 or succinyl-(Glu(9),Ala (11,15))-endothelin-1 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). It is a 15 amino acid long chain (Suc-Asp-Glu-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp) (Figure 1) and has very high selectivity for ETBRs with Ki values 0.016 and 1900 nM at ETBRs and ETARs receptors, respectively.…”