Functional Characterization of Spinocerebellar Ataxia Associated Dynorphin A Mutant Peptides

Biomedicines

Teresa Kaserer¹  Luca Zangrandi²  Germana Thaler²  Mitja Amon Posch²  Olga Trovato²  Andreas Lieb²  Barbara Fogli² 

[1] Center for Molecular Biosciences Innsbruck, Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, 6020 Innsbruck, Austria;Institute of Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria;

关键词: dynorphin;    kappa opioid receptor;    spinocerebellar ataxia;    β-arrestin;    G-protein;    functional selectivity;   

DOI  :  10.3390/biomedicines9121882

来源: DOAJ

【 摘 要 】

Mutations in the prodynorphin gene (PDYN) are associated with the development of spinocerebellar ataxia type 23 (SCA23). Pathogenic missense mutations are localized predominantly in the PDYN region coding for the dynorphin A (DynA) neuropeptide and lead to persistently elevated mutant peptide levels with neurotoxic properties. The main DynA target in the central nervous system is the kappa opioid receptor (KOR), a member of the G-protein coupled receptor family, which can elicit signaling cascades mediated by G-protein dissociation as well as β-arrestin recruitment. To date, a thorough analysis of the functional profile for the pathogenic SCA23 DynA mutants at KOR is still missing. To elucidate the role of DynA mutants, we used a combination of assays to investigate the differential activation of G-protein subunits and β-arrestin. In addition, we applied molecular modelling techniques to provide a rationale for the underlying mechanism. Our results demonstrate that DynA mutations, associated with a severe ataxic phenotype, decrease potency of KOR activation, both for G-protein dissociation as well as β-arrestin recruitment. Molecular modelling suggests that this loss of function is due to disruption of critical interactions between DynA and the receptor. In conclusion, this study advances our understanding of KOR signal transduction upon DynA wild type or mutant peptide binding.

【 授权许可】

Unknown