The concept of intramembrane receptor-receptor interactions and evidence for their existences were introduced in the beginning of the 1980's, suggesting the existence of receptor heterodimerization. The discovery of GPCR heteromers and the receptor mosaic (higher order oligomers, more than two) has been related to the parallel development and application of a variety of resonance energy transfer techniques such as bioluminescence (BRET), fluorescence (FRET) and sequential energy transfer (SRET). The assembly of interacting GPCRs, heterodimers and receptor mosaic leads to changes in the agonist recognition, signaling, and trafficking of participating receptors via allosteric mechanisms, sometimes involving the appearance of cooperativity. The receptor interface in the GPCR heteromers is beginning to be characterized and the key role of electrostatic epitope-epitope interactions for the formation of the receptor heteromers will be discussed. Furthermore, a "guide-and-clasp" manner of receptor-receptor interactions has been proposed where the "adhesive guides" may be the triplet homologies. These interactions probably represent a general molecular mechanism for receptor-receptor interactions. It is proposed that changes in GPCR function (moonlighting) may develop through the intracellular loops and C-terminii of the GPCR heteromers as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptors. The evidence for the existence of receptor heteromers opens up a new field for a better understanding of neurophysiology and neuropathology. Furthermore, novel therapeutic approaches could be possible based on the use of heteromers as targets for drug development based on their unique pharmacology.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.2174/092986712803414259 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
GPR88 impairs the signaling of kappa opioid receptors in a heterologous system and in primary striatal neurons.
Neuropharmacology
March 2025
Network Center for Biomedical Research in Neurodegenerative Diseases. CiberNed., Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029, Madrid, Spain; Molecular Neurobiology Laboratory, Dept. Biochemistry and Molecular Biomedicine, Facultat de Biologia, Universitat de Barcelona, 08028, Barcelona, Spain; School of Chemistry, Universitat de Barcelona, Barcelona, Spain. Electronic address:
Article Synopsis
- GPR88 is an orphan G protein-coupled receptor primarily found in the striatum, and its function is not well understood despite changes in its expression seen in Parkinson's disease models.
- GPR88 was found to interact with the kappa-opioid receptor (KOR), and this interaction inhibits KOR-mediated signaling, as evidenced by experiments showing that GPR88 can modulate effects of KOR agonists in both cultured cells and primary striatal neurons.
- The GPR88-KOR complexes were more common in specific neurons related to dopamine pathways, suggesting that understanding their relationship could have implications for conditions like neuropathic pain, Parkinson's disease, and neuropsychiatric disorders.
The cell adhesion molecule CD44 acts as a modulator of 5-HT7 receptor functions.
Cell Commun Signal
November 2024
Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.
Background: Homo- and heteromerization of G protein-coupled receptors (GPCRs) plays an important role in the regulation of receptor functions. Recently, we demonstrated an interaction between the serotonin receptor 7 (5-HT7R), a class A GPCR, and the cell adhesion molecule CD44. However, the functional consequences of this interaction on 5-HT7R-mediated signaling remained enigmatic.
View Article and Find Full Text PDFCannabinoid regulation of angiotensin II-induced calcium signaling in striatal neurons.
NPJ Parkinsons Dis
November 2024
Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Madrid, Spain.
Article Synopsis
- - Calcium ion (Ca) homeostasis is essential for proper neuron function, and this study investigated how the CB receptor (CBR) interacts with the ATR receptor to regulate cytoplasmic Ca levels in CNS neurons.
- - A specific type of interaction called AT-CB receptor heteromers (ATCBHets) was identified using bioluminescence resonance energy transfer (BRET) in lab cells and in the context of Parkinson's disease (PD).
- - The study found that activation of ATR reduces Ca levels in the presence of cannabinoids, and in a rat model of PD, lower levels of ATCBHets were linked to lesioned neurons, suggesting that cannabinoids might help mitigate calcium imbalance related to levodopa-induced
Measuring G protein activation by spectrally resolved imaging fluorescence fluctuation spectroscopy.
Biophys J
August 2024
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri. Electronic address:
The activation of heterotrimeric G proteins through G-protein-coupled receptors (GPCRs) is a ubiquitous signaling mechanism in eukaryotic biology. The three principal molecular components of this cascade are the GPCR, Gα subunit, and Gβγ subunit. Measurement of interactions between these components and their downstream effectors in live cells is paramount to understanding how cells fine-tune their physiology in response to many external stimuli.
View Article and Find Full Text PDFAllosterism in the adenosine A and cannabinoid CB heteromer.
Br J Pharmacol
July 2024
Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.
Article Synopsis
- Allosterism is a regulatory mechanism for G protein-coupled receptors (GPCRs) that can be affected by ligand binding or interactions between different GPCRs; the study focuses on the allosteric properties of A receptor and CB receptor when they form a heteromer.
- Experimental techniques used include measuring cAMP levels, analyzing phosphorylation of kinases, and using dynamic mass redistribution methods, showing how disrupting the heteromer affects receptor activation.
- Key findings reveal that the A receptor can inhibit signaling in the CB receptor by blocking essential structural components, and that certain antagonists can change the interaction dynamics to allow for receptor activation, highlighting a unique allosteric mechanism in GPCR signaling.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!