TABLE 1.

Summary of the main effects of PrP^C in synaptic function.

Binding interaction	Model	Functional role	Proposed mechanism of action	References
VGCC α2δ-1 subunit	Tg PG14 mice (CGNs) Xenopus oocytes and mammalian tsA-201 cells	Glutamatergic neurotransmission Modulation of Ca2+ currents	Promotes anterograde trafficking and secretory transport of VGCC channels to the cell membrane Downregulates CaV2.1/β4/α2δ-2 and CaV2.1/β1b/α2δ-1 channels in a GPI-anchoring form	Rutishauser et al., 2009; Senatore et al., 2012; Alvarez-Laviada et al., 2014
Kv4.2 DPP6 subunit	N2a, RK13, and HEK293T cells	Regulation of membrane excitability	Increases peak current amplitudes and the half-inactivation time of A-type K+ currents Regulates faster recovery time from steady-state inactivation of Kv4.2 channel	Schmitt-Ulms et al., 2004; Mercer et al., 2013
NMDAR NR1/NR2B subunits	Tga20 knock-in mice (hippocampal neurons) Prnp0/0 FVB/N and C57 mice	Neuroprotection Modulation of NMDAR activity	Downregulates NR2D subunits expression and S-nitrosylation of NMDAR Reduces glycine affinity, slows inactivation and current amplitudes of NMDAR	Khosravani et al., 2008a; Black et al., 2014; Gasperini et al., 2015; Huang et al., 2018
AMPAR GluA2 and GluA4 subunits	Cultured astrocytes from PrP–/– mice SH-SY5Y and N2a cells Hippocampal neurons from PrPC-overexpressed mice Tg PG14 and CJD mice	Glutamate-dependent lactate release Zinc uptake Non-affected AMPAR activity Neuronal survival	Regulates the MCT1-associated lactate transport and Na+/K+ pump astrocytic activity Zinc-sensitive tyrosine phosphatase activity NA Modulates secretory trafficking of AMPAR GluA2 subunit	Kleene et al., 2007; Khosravani et al., 2008b; Watt et al., 2012; Huang et al., 2018; Ghirardini et al., 2020
KARs GluR6/7 and PSD95 subunits	Prnp0/0 mice N2a cells Jnk30/0 mice	Neuroprotection against KA toxicity Neuronal survival	Regulates GluR6 and GluR7 mRNA levels Modulates KA-mediated neurotransmission Regulates PSD95/GluR6 complex	Rangel et al., 2007; Carulla et al., 2011, 2015
α7nAChR/STI1 complex	Hippocampal neurons HEK293 cells ZW 13-2 and Zpl 3-4 cell lines from Prnp–/– mice	Ca2+ homeostasis, neuritogenesis, and neuroprotection	Modulates positively α7nAChR activity PKA activity and ERK1/2 phosphorylation Regulates α7nAchR expression levels	Beraldo et al., 2010; Jeong and Park, 2015

PrP^C, cellular prion protein; CGNs, cerebellar granule neurons; CaV, voltage-gated Ca²⁺ channels; DPP6, dipeptidyl aminopeptidase-like protein 6; DPP6, dipeptidyl aminopeptidase-like protein 6; Kv, voltage-dependent K⁺ channels, FVB/N, Friend virus B-type susceptibility-NIH; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; MCT1, astroglial monocarboxylate transporter 1; CJD, Creutzfeldt–Jakob disease; KA, kainate; KARs, kainate receptor; N2a, murine neuroblastoma cell line Neuro2a; JNK3,c-Jun N-terminal kinase 3; PSD-95, postsynaptic density protein 95; α7nAChR, nicotinic acetylcholine receptor; STI1, stress-inducible protein 1; PKA, cAMP-dependent protein kinase 1; ERK1/2, extracellular signal-regulated kinase 1 and 2.