G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

Abstract

Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system (CNS) disorders. Many currently available antipsychotic therapeutics also act as either antagonists or agonists of different GPCRs. Therefore, GPCR-based drug development is spreading widely to regulate neurodegeneration and associated cognitive deficits through the modulation of canonical and noncanonical signals. Here, GPCRs' role in the pathophysiology of different neurodegenerative disease progressions and cognitive deficits has been highlighted, and an emphasis has been placed on the current pharmacological developments with GPCRs to provide an insight into a potential therapeutic target in the treatment of neurodegeneration.

Keywords: cannabinoid receptor; metabotropic glutamate receptor; orphan G-protein-coupled receptors; serotonin; seven transmembranes.

Figure 1

Schematic display of G-protein-coupled receptors (GPCRs) signalling in cognitive impairment. Depending on the agonist or inverse agonist ligand binding, the PI3/Akt-signalling pathway signals Bax and Casp-9 while increasing neurofibrillary tangle (NFT) formation via phosphorylation. PI3/Akt-signalling hyperphosphorylation also activates glycogen synthase kinase-3β (GSK-3β), which increases either or both tau protein phosphorylation and amyloid precursor protein (APP). Phosphorylated tau protein forms neurofibrillary tangles (NFTs) and regulates cognitive function. Similarly, APP metabolism regulates Aβ-plaque formation and controls cognition. Moreover, neuronal and dendritic plasticity is required for synaptic growth, regeneration, and memory formation, and it depends on extracellular signal-regulated kinase (ERK ½) modulation. Depending on the ligands, GPCRs activate cAMP-response element-binding protein (CREB) via the cAMP/ERK ½ pathway and regulate cognition (based on [20,21]).

Figure 2

Schematic display of allosteric modulator action on GPCRs. (A) Conventional agonist binding makes conformational changes and activates downstream signalling. Positive allosteric modulators bind to a distinct site and enhance conventional ligand-induced signalling. Negative allosteric modulators binding decreases conventional agonist efficacy and reduces downstream signalling. (B) In normal physiology, neurotransmitters are released into the synaptic cleft, binding to postsynaptic GPCRs, and activating downstream signalling. The duration of signalling can be degraded by metabolizing enzymes. A positive allosteric modulator (green rectangle) cobinding with the metabolites can extend the duration of receptor activation and enhance signalling (based on [177]).