Arrestins were discovered as the key proteins responsible for the shutoff of the G protein-dependent signaling by G protein-coupled receptors (GPCRs). Later it was discovered that arrestins regulate multiple signaling pathways, including mitogen activated protein (MAP) kinase pathways, by scaffolding the pathways’ components. One of the two ubiquitously expressed arrestin subtypes, arrestin-3, is the only isoform capable of activating the JNK pathway, with the preference for the JNK3 neuro specific isoform. We show that short peptides derived from the JNK3-binding region of arrestin-3 effectively mimic the full-length arrestin-3 protein in the ability to activate the JNK pathway. Further deletion of a few amino acids yields peptides that bind some, but not all kinases in the JNK pathway, thereby recruiting them away from productive arrestin-3-dependent scaffolds and inhibiting JNK3 activation via the dominant-negative mechanism. Therefore, such peptides should act as selective inhibitors of arrestin-3-dependent activation of JNK3. We recently found that arrestin-3-dependent JNK activation is a contributing factor to L-DOPA-induced dyskinesia (LID), a severe side effect of the most commonly used L-DOPA therapy in Parkinson’s disease. We show that lentivirus-mediated delivery of peptides activating JNK3 promote LID, whereas inhibitory peptides alleviate it in animal models of LID without interfering with the beneficial effect of L-DOPA. These data suggest that signaling peptides could be used as highly selective therapeutics for brain diseases. Such protein-derived peptides capable of fulfilling select functions of the parent multi-functional protein have a great potential as therapeutic tools, specifically to target protein-protein interactions, which are notoriously hard to modulate with small molecule therapeutics. We will show the data on the effectiveness of inhibitory arrestin-3-derived peptides rendered cell penetrating as anti-LID therapeutics. The issue of the best way of delivering the peptide therapeutics into the brain will be addressed.