Exploring Drug-Receptor Interaction Kinetics: Lessons from a Sigma-1 Receptor Transmembrane Biosensor

Fernández-Dueñas, Víctor; Burgueño, Javier; Ciruela, Francisco

doi:10.3389/fphar.2017.00004

Cited by 2 publications

(2 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…σ 1 R KO and age‐matched CB7L6j mice (8 weeks old, 23–28 g of weight) were kindly provided by Esteve Pharmaceuticals 10 . Under the current legislation, obtaining protocol approval is not needed if animals are sacrificed to obtain a specific tissue.…”

Section: Methodsmentioning

confidence: 99%

“…The marked increase of the extracellular concentration of dopamine in various regions of the brain leads to sensitization of dopamine receptors. Cocaine binds the sigma 1 receptor (σ 1 Rs), which is attracting interest for its potential as a therapeutic target in neuropathic pain, 10–12 although its physiological role remains unknown. From the recently elucidated 3D structures 13,14 we now know that the protein contains only one TM helix and forms homotrimers.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of a macromolecular complex mediating the hunger suppressive actions of cocaine: Structural and functional properties

et al. 2021

View full text Add to dashboard Cite

Cocaine not only increases brain dopamine levels but also activates the sigma1 receptor (σ1R) that in turn regulates orexigenic receptor function. Identification of interactions involving dopamine D1 (D1R), ghrelin (GHS‐R1a), and σ1 receptors have been addressed by biophysical techniques and a complementation approach using interfering peptides. The effect of cocaine on receptor functionality was assayed by measuring second messenger, cAMP and Ca2+, levels. The effect of acute or chronic cocaine administration on receptor complex expression was assayed by in situ proximity ligation assay. In silico procedures were used for molecular model building. σ1R KO mice were used for confirming involvement of this receptor. Upon identification of protomer interaction and receptor functionality, a unique structural model for the macromolecular complex formed by σ1R, D1R, and GHS‐R1a is proposed. The functionality of the complex, able to couple to both Gs and Gq proteins, is affected by cocaine binding to the σ1R, as confirmed using samples from σ1R−/− mice. The expression of the macromolecular complex was differentially affected upon acute and chronic cocaine administration to rats. The constructed 3D model is consistent with biochemical, biophysical, and available structural data. The σ1R, D1R, and GHS‐R1a complex constitutes a functional unit that is altered upon cocaine binding to the σ1R. Remarkably, the heteromer can simultaneously couple to two G proteins, thus allowing dopamine to signal via Ca2+ and ghrelin via cAMP. The anorexic action of cocaine is mediated by such complex whose expression is higher after acute than after chronic administration regimens.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%