Contents
Special Issue Topic

GPCR Heteroreceptor Complexes as Key Players in Neuroprotection

Submission Deadline: August 31, 2025

Guest Editor

Dr. Dasiel O. Borroto Escuela E-Mail

Department of Neuroscience, Karolinska Institutet, Biomedicum, B0851, Solnavagen 9. 17177 Stockholm, Sweden; Receptomics and Brain disorders lab, Department Of Human Physiology, Physical Education and Sport, Faculty of Medicine, University of Malaga, Malaga, Spain

Research Keywords: G protein coupled receptor; heteroreceptor complexes; neurodegeneration; neuroprotection; neurochemistry; neurobiology; biochemistry

About the Special lssue

The discovery and exploration of allosteric receptor-receptor interactions within G protein-coupled receptor (GPCR) heteroreceptor complexes in the central nervous system (CNS) have changed our understanding of brain integration and neuropsychopharmacology. These molecular interactions, particularly within postjunctional membranes of synapses, are proposed to underpin the molecular basis of learning and memory. The emergence of the GPCR heterodimer network (GPCR-HetNet) has demonstrated the significant impact of allosteric receptor-receptor interactions on GPCR diversity and recognition, thereby enhancing specificity in signaling. Dysregulation of GPCR heteroreceptor complexes is implicated in various brain disorders, presenting these complexes as critical players in neuroprotection. Investigations into serotonin (5-HT) hetero- and isoreceptor complexes over the past decade have uncovered novel targets for drug development, particularly in major depression. Neuromodulation of neuronal networks in depression involves a complex interplay of GPCR heteroreceptor complexes, such as GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer emerges as a pivotal component, enhancing antidepressant actions through its participation in various hetero- and homoreceptor complexes. In the context of cocaine use disorder, neuromodulation of neuronal networks via dopamine (DA) and adenosine signals engages A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and ventral striatum. Excitingly, the excitatory modulation by A2AR agonists of the ventral striato-pallidal GABA anti-reward system, targeting the A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complex, holds promise as a novel therapeutic avenue for treating cocaine use disorders. Additionally, investigations into schizophrenia reveal a complex interplay involving DA, adenosine, glutamate, 5-HT, neurotensin peptides, and oxytocin. Heteroreceptor complexes such as A2AR-D2R, D2R-NMDAR, A2AR-D2R-mGluR5, D2R-5-HT2A, and D2R-oxytocinR emerge as potential targets for the treatment of positive, negative, and cognitive symptoms of schizophrenia. This comprehensive exploration underscores the pivotal role of GPCR heteroreceptor complexes in the intricate landscape of neuroprotection and presents promising avenues for therapeutic interventions in various brain disorders.

Keywords: G protein-coupled receptors; allosteric interactions; oligomerization; receptor-receptor interactions; heteroreceptor complexes; mental disorders; neurodegeneration; neuroprotection

Published Articles

Open Access Review
Role of dopamine receptor heteromerization in preclinical models of addiction and other psychiatric disorders
Adèle Vilette ... Peter Vanhoutte
Published: April 01, 2025 Explor Neuroprot Ther. 2025;5:1004100
448 17 0
Open Access Review
Multilayered neuroprotection by cannabinoids in neurodegenerative diseases
Ahmed Hasbi, Susan R. George
Published: March 09, 2025 Explor Neuroprot Ther. 2025;5:100498
684 18 0
Open Access Review
Possible roles of heteroreceptor complexes in excitotoxic processes
Diego Guidolin ... Luigi F. Agnati
Published: September 24, 2024 Explor Neuroprot Ther. 2024;4:366–391
1243 31 1
Open Access Review
Lysophospholipid receptors in neurodegeneration and neuroprotection
Eric Birgbauer
Published: August 22, 2024 Explor Neuroprot Ther. 2024;4:349–365
1670 50 2