NMDA Receptor and L-Type Calcium Channel Modulate Prion Formation
Abstract
Transmissible neurodegenerative prion diseases are characterized by the conversion of the cellular prion protein (PrPC) to misfolded isoforms denoted as prions or PrP^(Sc). Although the conversion can occur in the test tube containing recombinant prion protein or cell lysates, efficient prion formation depends on the integrity of intact cell functions. Since neurons are main targets for prion replication, we asked whether their most specialized function, i.e. synaptic plasticity, could be a factor by which PrP^(Sc) formation can be modulated. Immortalized gonadotropin-releasing hormone cells infected with the Rocky Mountain Laboratory prion strain were treated with L-type calcium channels (LTCCs) and NMDA receptors (NMDARs) stimulators or inhibitors. Western blotting was used to monitor the effects on PrP^(Sc) formation in relation to ERK signalling. Infected cells showed enhanced levels of phosphorylated ERK (pERK) compared with uninfected cells. Exposure of infected cells to the LTCC agonist Bay K8644 enhanced pERK and PrP^(Sc) levels. Although treatment with an LTCC blocker (nimodipine) or an NMDAR competitive antagonist (D-AP5) had no effects, their combination reduced both pERK and PrP^(Sc) levels. Treatment with the non-competitive NMDAR channel blocker MK-801 markedly reduced pERK and PrP^(Sc) levels. Our study shows that changes in LTCCs and NMDARs activities can modulate PrP^(Sc) formation through ERK signalling. During synaptic plasticity, while ERK signalling promotes long-term potentiation accompanied by expansion of post-synaptic lipid rafts, other NMDA receptor-depending signalling pathways, p38-JNK, have opposing effects. Our findings indicate that contrasting intracellular signals of synaptic plasticity can influence time-dependent prion conversion.
Additional Information
© 2020 Springer Nature Switzerland AG. Received 20 December 2019; Accepted 22 March 2020; Published 01 April 2020. The authors acknowledged SISSA intramural grant support for carrying out the study. This study was supported by Intra-mural SISSA funding. Author Contributions: K.K., G.F. and G.L. conceived and designed the study, M.Z., C.G., E.X. and G.S. performed the experimental work, M.Z., K.K., G.F. and G.L. analyzed data, M.Z., K.K. and G.L. wrote the manuscript. All authors approved the final version of the manuscript. The authors declare that they have no competing interests. Research Involving Human Participants and/or Animals: This article does not contain any studies with human participants or animals performed by any of the authors. Informed Consent: Not applicable.Attached Files
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Additional details
- Eprint ID
- 102339
- DOI
- 10.1007/s10571-020-00834-1
- Resolver ID
- CaltechAUTHORS:20200406-082620773
- Scuola Internazionale Superiore di Studi Avanzati (SISSA)
- Created
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2020-04-06Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field