A pivotal role of FOS-mediated BECN1/Beclin 1 upregulation in dopamine D2 and D3 receptor agonist-induced autophagy activation

Abstract

Autophagy dysfunction is implicated in the pathogenesis of Parkinson disease (PD). BECN1/Beclin 1 acts as a critical regulator of autophagy and other cellular processes; yet, little is known about the function and regulation of BECN1 in PD. In this study, we report that dopamine D2 and D3 receptor (DRD2 and DRD3) activation by pramipexole and quinpirole could enhance BECN1 transcription and promote autophagy activation in several cell lines, including PC12, MES23.5 and differentiated SH-SY5Y cells, and also in tyrosine hydroxylase positive primary midbrain neurons. Moreover, we identified a novel FOS (FBJ murine osteosarcoma viral oncogene homolog) binding sequence (5′-TGCCTCA-3′) in the rat and human Becn1/BECN1 promoter and uncovered an essential role of FOS binding in the enhancement of Becn1 transcription in PC12 cells in response to the dopamine agonist(s). In addition, we demonstrated a critical role of intracellular Ca2+ elevation, followed by the enhanced phosphorylation of CAMK4 (calcium/calmodulin-dependent protein kinase IV) and CREB (cAMP responsive element binding protein) in the increases of FOS expression and autophagy activity. More importantly, pramipexole treatment ameliorated the SNCA/α-synuclein accumulation in rotenone-treated PC12 cells that overexpress wild-type or A53T mutant SNCA by promoting autophagy flux. This effect was also demonstrated in the substantia nigra and the striatum of SNCAA53T transgenic mice. The inhibition of SNCA accumulation by pramipexole was attenuated by cotreatment with the DRD2 and DRD3 antagonists and Becn1 siRNAs. Thus, our findings suggest that DRD2 and DRD3 agonist(s) may induce autophagy activation via a BECN1-dependent pathway and have the potential to reduce SNCA accumulation in PD.

MicroRNA-93 mediates cabergoline resistance by targeting ATG7 in prolactinoma

“…to the CAB treatment (Gillam et al 2006, Wu et al 2016b, and the treatment of drug-resistant prolactinomas remains a challenging clinical problem. Accumulating evidence has proven that DAs, such as CAB, play a vital role in inducing autophagic cell death (Wang et al 2015. Wang et al (2015) reported that D2R/D3R agonist(s) might activate autophagy through the BECN1-dependent pathway and inhibit the tumor growth in A549 cells.…”

Activation of AMPK‐dependent autophagy in the nucleus accumbens opposes cocaine‐induced behaviors of mice

“…Several studies have observed that autophagy is evident after dopamine treatment for 6 h . The D 2 R and D 3 R agonists pramipexole (PPX) and quinpirole induce autophagy activation . Ammonia‐induced autophagy by mTOR‐inhibition is mediated by D 3 R .…”

“…However, the molecular mechanism for the regulation of autophagy by dopamine is poorly studied. A recent study suggests that the increased Ca 2+ level may be involved in the autophagy induction, which is mediated by D 2 R and D 3 R . So far, there remains controversy over the role of Ca 2+ in modulating autophagy activity .…”

c‐Jun expression after cerebral hyperstimulation differs between rats and marmosets

“…The sections were processed for the immunohistochemical detection of c‐Jun protein using a conventional avidin–biotin immunoperoxidase technique to localize an antiserum raised against a c‐Jun protein (rabbit polyclonal, Santa Cruz—catalog number: sc‐1694; ). Specificity of this antibody for c‐Jun as compared to other Jun family proteins has been recently evaluated (Yamazaki et al, ), as well as its ability to recognize c‐Jun from several species (Kurashige et al, ; Ogawa et al, ; Wang et al, ). Briefly, free‐floating sections were pretreated with hydrogen peroxidase for 10 min.…”