GPR88, or G protein-coupled receptor 88, is a protein of growing scientific interest. Researchers are actively studying its unique characteristics and functions to understand its role in various biological processes and its potential association with health conditions.
The Basics of GPR88
GPR88 is an orphan G protein-coupled receptor (GPCR), meaning its natural activator, or “ligand,” has not yet been identified. This receptor is encoded by the GPR88 gene and is a multi-pass membrane protein found on the cell membrane.
GPR88 is predominantly found in the brain, with robust expression in the striatum. The striatum is a brain structure that plays a significant role in controlling motor function and cognition. GPR88 is also expressed at lower levels in other brain regions, including the cerebral cortex, central extended amygdala, lateral hypothalamus, and olfactory tubercles.
GPR88’s Role in Brain Function
GPR88 regulates various brain and behavioral functions, including cognition, mood, movement control, and reward-based learning. It couples with the heterotrimeric G protein complex of the G(i) subfamily, which allows it to inhibit adenylyl cyclase and reduce cyclic AMP (cAMP) production and signaling.
The receptor is highly expressed in medium spiny neurons (MSNs) of the striatum, which are the primary input neurons of the basal ganglia. This positioning allows GPR88 to modulate the excitability of both glutamatergic and GABAergic neurons, as well as influencing responses to dopaminergic neurons. GPR88 can also influence the signaling of other GPCRs, including opioid receptors, potentially dampening their activity.
GPR88 and Neurological Conditions
Dysfunction or altered expression of GPR88 has been linked to several neurological and psychiatric disorders. GPR88 is considered a potential target for central nervous system disorders such as schizophrenia, Parkinson’s disease, Huntington’s disease, anxiety, bipolar disorder, depression, and drug addiction. Genetic studies in humans also link GPR88 function to conditions like speech delay and chorea.
In Parkinson’s disease, for example, dopamine depletion in the striatum can alter GPR88 expression in MSNs. Research using GPR88 knockout mice has shown altered motor functions and increased voluntary alcohol drinking, suggesting a role in alcohol use disorder. GPR88 is also being investigated for its contribution to impulse control disorders and attention-deficit/hyperactivity disorder (ADHD), with animal studies indicating that deficient GPR88 activity can promote ADHD-like behaviors.
Therapeutic Potential of GPR88
Given its widespread influence on brain function and its implication in various neurological conditions, GPR88 is being investigated as a promising target for drug development. Developing pharmacological agents that can either activate (agonists) or block (antagonists) GPR88 is key to restoring normal brain function. Several GPR88 agonists, such as 2-PCCA and RTI-13951–33, have been identified and are in early preclinical studies.
Translating this research into new therapies presents both opportunities and challenges. While GPR88’s restricted expression primarily in the brain makes it an attractive target, the lack of identified endogenous ligands complicates drug discovery. Further research in GPR88 pharmacology, medicinal chemistry, and chemical biology is needed to develop a wider range of specific compounds and to fully understand the receptor’s signaling pathways.