DRD3 (dopamine receptor D3) but not DRD2 activates autophagy through MTORC1 inhibition preserving protein synthesis

Abstract

Growing evidence shows that autophagy is deficient in neurodegenerative and psychiatric diseases, and that its induction may have beneficial effects in these conditions. However, as autophagy shares signaling pathways with cell death and interferes with protein synthesis, prolonged use of autophagy inducers available nowadays is considered unwise. The search for novel autophagy inducers indicates that DRD2 (dopamine receptor 2)-DRD3 ligands may also activate autophagy, though critical aspects of the action mechanisms and effects of dopamine ligands on autophagy are still unknown. In order to shed light on this issue, DRD2and DRD3-overexpressing cells and drd2 KO, drd3 KO and wild-type mice were treated with the DRD2-DRD3 agonist pramipexole. The results revealed that pramipexole induces autophagy through MTOR inhibition and a DRD3-dependent but DRD2-independent mechanism. DRD3 activated AMPK followed by inhibitory phosphorylation of RPTOR, MTORC1 and RPS6KB1 inhibition and ULK1 activation. Interestingly, despite RPS6KB1 inhibition, the activity of RPS6 was maintained through activation of the MAPK1/3-RPS6KA pathway, and the activity of MTORC1 kinase target EIF4EBP1 along with protein synthesis and cell viability, were also preserved. This pattern of autophagy through MTORC1 inhibition without suppression of protein synthesis, contrasts with that of direct allosteric and catalytic MTOR inhibitors and opens up new opportunities for G protein-coupled receptor ligands as autophagy inducers in the treatment of neurodegenerative and psychiatric diseases.

A Re-Appraisal of Pathogenic Mechanisms Bridging Wet and Dry Age-Related Macular Degeneration Leads to Reconsider a Role for Phytochemicals

“…Intriguingly, approaches promoting POS degradation through lysosomes re-acidification within impaired RPE cells include stimulation of beta-2 adrenergic, A2A adenosine, and D5 dopamine receptors [ 118 ]. This is interesting since adenosine, norepinephrine, and dopamine, which play a role in retinal function and POS phagocytosis [ 118 , 119 , 120 , 121 , 122 ], are known to variously affect mTOR-, AMPK-, and TFEB-related autophagy and also the proteasome system through stimulation of beta-adrenergic, A2A adenosine, and D1/D2-like dopamine receptors [ 123 , 124 , 125 , 126 , 127 , 128 , 129 ]. Since autophagy–lysosomal dysfunction associated with either an increased activity of mTORC1 or decreased activity of AMPK or TFEB does predispose to RPE and photoreceptors degeneration in experimental models [ 36 , 97 , 129 , 130 , 131 , 132 ], it would be worth investigating whether a coupling between alterations of autophagy activity and catecholamine innervation occurs in the frame of AMD.…”

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

“…O-6-methylguanine-DNA methyltransferase (MGMT) is a type of suicide DNA damage repair enzymes, and DNA damage repair disorders have been reported to induce autophagy (Balvers et al, 2015;Abdu et al, 2020). Lei et al (2020) have found that the high expression of MGMT is significantly correlated with the low expression of ATG4B and the favorable prognosis of gastric cancer.…”

“…Under the depletion of nutrients and energy with the increasing AMP/ATP ratio, LKB1 (liver kinase B1), a tumor suppressor kinase, stimulates the activation of AMPK, which subsequently promotes the formation of TSC1/TSC2 complex to inactivate mTORC1 and induce autophagy ( Figure 3 ) ( Bakula et al, 2017 ). Moreover, AMPK can inhibit mTORC1 by directly phosphorylating Raptor ( Barroso-Chinea et al, 2020 ). Under the undernourished condition, AMPK can directly phosphorylate ULK1 at Ser317, S467, S555, S574, S637, and Ser777 by separating mTORC1 from ULK1 and stimulate autophagy ( Zachari and Ganley, 2017 ), whereas mTORC1 can block the function of AMPK by phosphorylating ULK1 under the glucose abundant condition ( Mao and Klionsky, 2011 ).…”

Autophagy-Based Hypothesis on the Role of Brain Catecholamine Response During Stress

“…This is associated with neuroprotection and inhibition of alpha-synuclein/SNCA accumulation both in rotenone-treated catecholamine-containing cells that overexpress wild-type or mutant alpha-synuclein and in SNCA transgenic mice ( 76 ). More recently, D3DRs were shown to be specifically responsible for autophagy activation via AMPK stimulation and mTOR inhibition ( 77 ).…”