G-protein coupled receptors in neuroinflammation, neuropharmacology, and therapeutics

The G protein-coupled receptors (GPCRs) represent one of the most pharmacologically targeted classes of seven-transmembrane (7TM) receptors, identified through whole genome sequencing of humans. GPCRs transduce extracellular stimuli and signals into intracellular responses, enabling precise cellular communication for physiology and homeostasis. Given their ability to sense a variety of ligands, GPCRs regulate a plethora of physiological functions, such as sensory perception, hormonal regulation and metabolism, growth and development, cardiovascular and reproductive regulation. GPCRs also orchestrate immune responses, triggering a balanced pro- and anti-inflammatory signaling, which is linked to the development, differentiation, and regulation of B-cells that are responsible for the secretion of infection-fighting antibodies. However, an imbalance in inflammatory signaling is also linked to disruption of B-cell differentiation, leading to autoimmune diseases due to increased levels of autoantibodies. Additionally, GPCRs modulate neurotransmission and synaptic plasticity, influencing behaviour, mood, and cognitive functions. Due to their diverse functionality, ∼40 % of FDA-approved, currently marketed drugs are reported to target different GPCRs for therapeutic benefit. A focal point of this review is GPCR-driven neuroinflammation, particularly in neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, including others. The review highlights the contribution of the pro- and anti-inflammatory GPCRs in modulating the disease pathophysiology, including the existing and emerging therapies. It also provides a future roadmap for alternative drug discovery for suppressing neuroinflammation-mediated neurodegenerative disease.