Towards the convergent therapeutic potential of G protein‐coupled receptors in autism spectrum disorders

Abstract

Autism spectrum disorders (ASD) are diagnosed in 1/100 children worldwide, based on two core symptoms, deficits in social interaction and communication and stereotyped behaviours. G protein‐coupled receptors (GPCRs) are the largest family of cell‐surface receptors that transduce extracellular signals to convergent intracellular signalling and downstream cellular responses that are commonly dysregulated in ASD. Despite hundreds of GPCRs being expressed in the brain, only 23 are genetically associated with ASD according to the Simons Foundation Autism Research Initiative (SFARI) gene database: oxytocin OTR, vasopressin V1A, V1B, metabotropic glutamate mGlu5, mGlu7, GABAB2, dopamine D1, D2, D3, serotoninergic 5‐HT1B, β2‐adrenoceptor, cholinergic M3, adenosine A2A, A3, angiotensin AT2, cannabinoid CB1, chemokine CX3CR1, orphan GPR37, GPR85 and olfactory OR1C1, OR2M4, OR2T10, OR52M1. Here, we review the therapeutic potential of these 23 GPCRs, 5‐HT2A and 5‐HT7 for ASD. For each GPCR, we discuss its genetic association, genetic and pharmacological manipulation in animal models, pharmacopeia for core symptoms of ASD and rank them based on these factors. Among these GPCRs, we highlight that D2, 5‐HT2A, CB1, OTR and V1A are the most promising targets for ASD. We discuss that the dysregulation of GPCRs and their signalling is a convergent pathological mechanism of ASD. Their therapeutic potential has only begun as multiple GPCRs could mitigate ASD.

Effect of Schizophrenia linkedDRD2gene mutations and correlation of social behavior with biochemical changes in a post-weaning isolated mouse model

“…Our in silico analysis in the current study demonstrates the effect of the mutations in different genes related to neurological conditions on their encoded protein structures and predicted the possible alteration in synaptic signaling, specifically the DRD2 . In addition to its schizophrenia association, DRD2 is one of the strongest candidates linked to ASD, and targeting its activity might be a potential therapeutic strategy (Annamneedi et al, 2023). Further studies are required to address the altered interaction between Neuronal calcium sensor 1 and D(2) dopamine receptor, due to the mutation and its relevance to both schizophrenia and ASD and in developing the common therapeutic strategies.…”

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

“…mGluR5 antagonists have been the only class of glutamatergic modulators that has made significant advances in drug development for the treatment of ASD. However, despite the enthusiasm raised due to their success in preclinical phases, unfortunately mGluR5 antagonists have failed in phase III clinical trials on ASD patients for lack of efficacy [ 43 , 44 ].…”

Transcriptome Study in Sicilian Patients with Autism Spectrum Disorder

“…G Protein-Coupled Receptors (GPCRs) constitute the largest family of cell-surface receptors that transmit extracellular signals to convergent intracellular signaling pathways and downstream cellular responses, which are frequently dysregulated in ASD. They play pivotal roles in various physiological processes, including sensory perception (such as taste, smell, and vision), neurotransmission, hormone regulation, and immune response [61].…”

“…Recent genome association studies of large ASD cohorts have robustly identified two major convergent neurobiological mechanisms: gene expression regulation or neuronal communication, and localization or plasticity [63][64][65]. Moreover, pharmacological interventions targeting GPCRs hold considerable therapeutic potential for ASD [61].…”

“…Additionally, Annamneedi et al (2023) [61] revealed that GPCRs and their downstream signaling pathways are affected by ASD. GPCRs respond to various natural signals, including photons, amino acids, peptides, and large glycosylated proteins.…”