Arrestin-3-assisted activation of JNK3 mediates dopaminergic behavioral and signaling plasticity in vivo.

Autor:	Ahmed MR; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Zheng C; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Dunning JL; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Ahmed MS; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Ge C; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Sanders Pair F; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Gurevich VV; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Gurevich EV; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 30. Date of Electronic Publication: 2023 Oct 30.
DOI:	10.1101/2023.10.27.564447
Abstrakt:	In rodents with unilateral ablation of the substantia nigra neurons supplying dopamine to the striatum, chronic treatment with the dopamine precursor L-DOPA or dopamine agonists induces a progressive increase of behavioral responses, a process known as behavioral sensitization. The sensitization is blunted in arrestin-3 knockout mice. Using virus-mediated gene delivery to the dopamine-depleted striatum of arrestin-3 knockout mice, we found that the restoration of arrestin-3 fully rescued behavioral sensitization, whereas its mutant defective in JNK activation did not. A 25-residue arrestin-3-derived peptide that facilitates JNK3 activation in cells, expressed ubiquitously or selectively in the direct pathway striatal neurons, fully rescued sensitization, whereas an inactive homologous arrestin-2-derived peptide did not. Behavioral rescue was accompanied by the restoration of JNK3 activity and of JNK-dependent phosphorylation of the transcription factor c-Jun in the dopamine-depleted striatum. Thus, arrestin-3-dependent JNK3 activation in direct pathway neurons is a critical element of the molecular mechanism underlying sensitization. Competing Interests: Disclosures. Eugenia V. Gurevich and Vsevolod V. Gurevich have a patent related to this work: “PEPTIDE REGULATORS OF JNK FAMILY KINASES” Patent No.: US 10,369,187 B2, Date of Patent: Aug. 6, 2019. The authors declare no other competing interests.
Databáze:	MEDLINE
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