GPR88

Official Full Name

G protein-coupled receptor 88

Organism

Homo sapiens

GeneID

54112

Background

The protein encoded by this gene is a G protein-coupled receptor found almost exclusively in the striatum, a brain structure that controls motor function and cognition. Defects in this gene have been associated with chorea, speech delay, and learning difficulties, as well as some neuropsychiatric disorders. [provided by RefSeq, Mar 2017]

Synonyms

STRG; COCPMR;

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Detailed Information

The Gpr88 gene was first discovered in 2000 by the Ito lab by using differential display screening for region-specific transcripts in rat brain. The Gpr88 gene encodes a seven transmembrane spanning receptor protein (GPR88), an orphan GPCR of the class A rhodopsin family of receptors.

GPR88 is predominantly expressed in striatal projection neurons, with high evolutionary conservation between humans and rodents in both primary structure and expression pattern, showing critical functional conservation. Associated with the reward network in the striatum, GPR88 has been implicated in numerous behaviors linked to neurological conditions in both rodents and humans, namely bipolar disorders, schizophrenia, responses to psychostimulant drugs and antidepressants, as well as learning and social behavior. In addition to the abundant distribution throughout the striatum including the nucleus accumbens (Acb), caudate putamen (CPu) and olfactory tubercle, GPR88 expression is also enriched in inferior olive in the brainstem, amygdala and cortex, with minimal to absent expression in peripheral tissues. Interestingly, many of the GPR88-rich areas are involved in the reward processing system that is integrated and interrelated with the circuits controlling energy balance to direct downstream effects on appetite and food intake.

The molecular signaling pathway of GPR88 was initially described using small molecule agonists for the receptor. These studies indicated GPR88 couples to Gαi/o G proteins, allowing GPR88 to inhibit adenylyl cyclase and reduce cAMP production and signaling (Figure 1). GPR88 knockout mice also have provided important hints about the receptors potential signaling in the brain. For example, using striatal membranes from Gpr88 KO mice revealed loss of GPR88 receptor expression inhibited the function of opioid (δ/μ) and muscarinic acetylcholine receptors (M1/M4) coupling to Gi/Go proteins, and possibly the signaling of other GPCRs at the cellular level. Further in vivo studies revealed functional antagonism between GPR88 and δ-opioid receptor (DOR) activities. Also, electrophysiological studies in Gpr88 KO mice demonstrated that the absence of GPR88 increased glutamatergic excitation and reduced GABAergic inhibition in striatal MSNs. This work further suggests GPR88 is inhibitory in the striatum, and when knocked out, striatal neuron firing rates increase in vivo.

Figure 1. GPR88 signaling pathway.

Evidence of GPR88 function, including knockout studies and transcriptional profiling studies, indicates GPR88 may provide a druggable target for human CNS diseases involving the striatum. GPCRs are notoriously challenging for crystallography and require either significant protein engineering or nanobody stabilization and the vast majority of current GPCR-ligand structures are with antagonists. Therefore, discovery and optimization of a high affinity GPR88 antagonist could empower future structural studies of the receptor. Currently identified synthetic GPR88 agonists, represented by 2-PCCA and 2-AMPP, have limited translational and clinical development potential due to various suboptimal drug-like properties, including high lipophilicity, suboptimal target selectivity and poor metabolic stability. Further diligent and iterative efforts on hit-to-lead optimization will be needed to improve current leads for their drug-like properties, especially their in vivo drug metabolism and pharmacokinetics (DMPK) properties. Moreover, with recent discoveries of orphan GPCR signaling pathways and physiological functions and novel screening approaches, deorphanization campaigns can be redesigned to better capture the native signaling of orphan receptors. Both deorphanization and continued probe development will accelerate understanding of GPR88 biological functions, facilitate evaluation of GPR88 as a drug target, and open new avenues for potential neurotherapeutics.

References:

Meirsman A C, et al. GPR88 in A2AR-neurons enhances anxiety-like behaviors. Eneuro, 2016.
Lau J, et al. GPR88 is a critical regulator of feeding and body composition in mice. Sci Rep, 2017, 7(1).
Ye N, et al. Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target. ACS chemical neuroscience, 2018, 10(1): 190-200.
Lovinger D M. New twist on orphan receptor GPR88 function. Nature neuroscience, 2012, 15(11): 1469.

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