| First Author | Pallaki P | Year | 2017 |
| Journal | Neuropharmacology | Volume | 117 |
| Pages | 408-421 | PubMed ID | 28219718 |
| Mgi Jnum | J:329727 | Mgi Id | MGI:6838171 |
| Doi | 10.1016/j.neuropharm.2017.02.012 | Citation | Pallaki P, et al. (2017) A novel regulatory role of RGS4 in STAT5B activation, neurite outgrowth and neuronal differentiation. Neuropharmacology 117:408-421 |
| abstractText | The Regulator of G protein Signalling 4 (RGS4) is a multitask protein that interacts with and negatively modulates opioid receptor signalling. Previously, we showed that the delta-opioid receptor (delta-OR) forms a multiprotein signalling complex consisting of Gi/Go proteins and the Signal Transducer and Activator of Transcription 5B (STAT5B) that leads to neuronal differentiation and neurite outgrowth upon delta-OmicronR activation. Here, we investigated whether RGS4 could participate in signalling pathways to regulate neurotropic events. We demonstrate that RGS4 interacts directly with STAT5B independently of delta-OmicronR presence both in vitro and in living cells. This interaction involves the N-terminal portion of RGS4 and the DNA-binding SH3 domain of STAT5B. Expression of RGS4 in HEK293 cells expressing delta-OR and/or erythropoietin receptor results in inhibition of [D-Ser(2), Leu(5), Thr(6)]-enkephalin (DSLET)-and erythropoietin-dependent STAT5B phosphorylation and subsequent transcriptional activation. DSLET-dependent neurite outgrowth of neuroblastoma cells is also blocked by RGS4 expression, whereas primary cortical cultures of RGS4 knockout mice (RGS4(-/-)) exhibit enhanced neuronal sprouting after delta-OR activation. Additional studies in adult brain extracts from RGS4(-/-) mice revealed increased levels of p-STAT5B. Finally, neuronal progenitor cultures from RGS4(-/-) mice exhibit enhanced proliferation with concomitant increases in the mRNA levels of the anti-apoptotic STAT5B target genes bcl2 and bcl-xl. These observations suggest that RGS4 is implicated in opioid dependent neuronal differentiation and neurite outgrowth via a "non-canonical" signaling pathway regulating STAT5B-directed responses. |
