Regulation of proteasome activity by P2Y2 receptor underlies the neuroprotective effects of extracellular nucleotides



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Diego García, Laura de and Ramírez Escudero, Mercedes and Sebastián Serrano, Álvaro and Díaz Hernández, Juan Ignacio and Pintor, Jesús and Lucas Lozano, José J. and Díaz Hernández, Miguel (2017) Regulation of proteasome activity by P2Y2 receptor underlies the neuroprotective effects of extracellular nucleotides. Bioquimica et biophysica acta, 1863 (1). pp. 43-51. ISSN 0006-3002

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The Ubiquitin-Proteasome System (UPS) is essential for the regulation of the cellular proteostasis. Indeed, it has been postulated that an UPS dysregulation is the common mechanism that underlies several neurological disorders. Considering that extracellular nucleotides, through their selective P2Y2 receptor (P2Y2R), play a neuroprotective role in various neurological disorders that course with an UPS impairment, we wonder if this neuroprotective capacity resulted from their ability to modulate the UPS. Using a cellular model expressing two different UPS reporters, we found that the stimulation of P2Y2R by its selective agonist Up4U induced a significant reduction of UPS reporter levels. This reduction was due to an increase in two of the three peptidase proteasome activities, chymotrypsin and postglutamyl, caused by an increased expression of proteasome constitutive catalytic subunits β1 and β5. The intracellular signaling pathway involved required the activation of IP3/MEK1/2/ERK but was independent of PKC or PKA. Interestingly, the P2Y2R activation was able to revert both UPS-reporter accumulation and the cell death induced by a prolonged inhibition of UPS. Finally, we also observed that intracerebroventricular administration of Up4U induced a significant increase both of chymotrypsin and postglutamyl activities as well as an increased expression of proteasome subunits β1 and β5 in the hippocampus of wild-type mice, but not in P2Y2R KO mice. All these results strongly suggest that the capacity to modulate the UPS activity via P2Y2R is the molecular mechanism which is how the nucleotides play a neuroprotective role in neurological disorders.

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Received 23 June 2016, Revised 22 September 2016, Accepted 16 October 2016, Available online 18 October 2016.

Uncontrolled Keywords:Chymotrypsin-like activity; Neurological disorders; P2Y2 receptor; Postglutamyl-like activity; Ubiquitin-proteasome-system; Up4U
Subjects:Sciences > Chemistry > Biochemistry
Medical sciences > Medicine > Physiology
Medical sciences > Medicine > Neurosciences
Medical sciences > Biology > Molecular biology
ID Code:45087
Deposited On:13 Oct 2017 07:55
Last Modified:16 Oct 2017 08:13

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