Oligomeric molecular construction of the MOR-Gal1R advanced revealed
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A examine printed within the journal Pharmacological Research reveals the oligomeric molecular construction of the MOR-Gal1R advanced, a element current within the mind which is concerned within the analgesic and addictive results of sure opioids.

The examine consists of the participation of the consultants Vicent Casadó, Estefanía Moreno and Verònica Casadó-Anguera, from the Molecular Neuropharmacology Research Group of the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB).

The examine is coordinated by the consultants Vicent Casadó (UB-IBUB), Leonardo Pardo (UAB), Leigh Daniel Plant (Boston Northeastern University, United States) and Sergi Ferré (National Institute on Drug Abuse, NIH, United States).

This preclinical examine, based mostly on the usage of mobile fashions and main biophysical, biochemical and pharmacological strategies (complete inside reflection fluorescence microscopy, TIRF), has been distinguished for its scientific curiosity within the web site of the NIH’s National Institute on Drug Abuse.

Receptors, macrostructures and pharmacological exercise

Gal1R and MOR receptors belong to the household of G protein-coupled receptors (GPCRs) that participate within the transduction of various mobile indicators and the management of important cell features. These constructions can type dimers —homodimers or heterodimers— that decide purposeful and pharmacological properties which can be totally different from these of the person parts.

The examine exhibits totally different in vitro evidences that reveal the choice of Gal1R and MOR receptors to type homodimeric complexes (MOR-MOR or Gal1R-Gal1R) in cell cultures when they’re expressed individually. When expressed collectively, tetrameric complexes (heterotetramers) are shaped by homodimers of each receptors (MOR-MOR-Gal1R-Gal1R-Gal1R).

This heterotetrameric construction is much more advanced as a result of when the homodimers of each receptors be part of to type the MOR-MOR macrocomplex, the interplay and corresponding signaling is maintained via their attribute G protein (the G protein inhibitory to adenylate cyclase or Gi).”

Vicent Casadó, Member of the Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona

“However, Gal1R-Gal1R exchanges its characteristic inhibitory G-protein for the adenylyl cyclase-stimulating G-protein (Gs). This higherorder oligomeric complex contains more than 10 protein subunits considering the four receptors, the two heterotrimeric G-proteins and the adenylyl cyclase enzyme on which both G-proteins act to up- or down-regulate the intracellular levels of the cyclic AMP messenger”, provides the knowledgeable.

Determining the molecular traits of this macrostructure would clarify the molecular mechanism by which the neuropeptide galanin —which has neurotrophic and neuroprotective properties— causes a lower within the launch of dopamine into the nucleus accumbens induced by opioids, as described by the identical staff (Journal of Neuroscience, 2016).

“This would be possible because when the Gal1R ligand binds to the heteromer, it activates the Gs protein, which interacts with the same adenylyl cyclase that was inhibited by the MOR-activated Gi protein, so it counteracts the secondary effects that opioid ligands have in activating the MOR receptors in the ventral tegmental area”, says researcher Estefanía Moreno, member of the Department of Biochemistry and Molecular Biomedicine and IBUB.

Searching for brand spanking new non-addictive medication

In earlier research, the staff from the Faculty of Biology and the IBUB had already confirmed that the larger proportion of analgesic —and never euphoric— results of methadone administration make this compound essentially the most indicated non-addictive possibility for the remedy of persistent ache (Journal of Clinical Investigation, 2019). This might be defined by the truth that methadone acts preferentially on MOR receptors when they don’t type heteromers with Gal1R receptors, and due to this fact, its impact is principally peripheral.

“Now, knowing this tetrameric macrostructure of the receptor complex —in addition to the differential capacities of opioid ligands to activate MOR depending on the formation of oligomeric complexes with other receptors— will facilitate the future design of opioid drugs that can bind with a greater affinity or can bind more effectively the signal pathways with mu-opioid receptor homodimers than with the MOR-Gal1R heterotetramers”, notes researcher Verònica Casadó-Anguera.

Specifically, it could be about μ-opioid receptor medication able to discriminating between homodimers of those compounds and their heterotetramers with galanin receptors. “It is also possible to design a strategy that combines opioid ligands with Gal1R ligands that bind to the heterotetramer and inhibit the activation of the dopamine system and, therefore, addiction. Thus, these therapies are expected to have a greater analgesic effect and less addictive activity”, concluded the analysis staff.


Journal reference:

De Oliverira, P. A., et al. (2022) Preferential Gs protein coupling of the galanin Gal1 receptor within the µ-opioid-Gal1 receptor heterotetramer. Pharmacological Research. doi.org/10.1016/j.phrs.2022.106322

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