Role of α7 Nicotinic Acetylcholine Receptor in Calcium Signaling Induced by Prion Protein Interaction with Stress-inducible Protein 1

Abstract

The prion protein (PrP C ) is a conserved glycosylphosphatidylinositol-anchored cell surface protein expressed by neurons and other cells. Stress-inducible protein 1 (STI1) binds PrP C extracellularly, and this activated signaling complex promotes neuronal differentiation and neuroprotection via the extracellular signal-regulated kinase 1 and 2 (ERK1/2) and cAMP-dependent protein kinase 1 (PKA) pathways. However, the mechanism by which the PrP C -STI1 interaction transduces extracellular signals to the intracellular environment is unknown. We found that in hippocampal neurons, STI1-PrP C engagement induces an increase in intracellular Ca 2؉ levels. This effect was not detected in PrP C -null neurons or wild-type neurons treated with an STI1 mutant unable to bind PrP C . Using a best candidate approach to test for potential channels involved in Ca 2؉ influx evoked by STI1-PrP C , we found that ␣-bungarotoxin, a specific inhibitor for ␣7 nicotinic acetylcholine receptor (␣7nAChR), was able to block PrP C -STI1-mediated signaling, neuroprotection, and neuritogenesis. Importantly, when ␣7nAChR was transfected into HEK 293 cells, it formed a functional complex with PrP C and allowed reconstitution of signaling by PrP C -STI1 interaction. These results indicate that STI1 can interact with the PrP C ⅐␣7nAChR complex to promote signaling and provide a novel potential target for modulation of the effects of prion protein in neurodegenerative diseases.Prions are the infectious components of transmissible spongiform encephalopathies that can self-perpetuate by imprinting an anomalous conformation onto a glycosylphosphatidylinositol-anchored host protein known as the prion protein (PrP C ). 3Conversion of PrP C to the protease-resistant prion is thought to be a major event in prion diseases (1). However, despite the wealth of knowledge on prions, the roles of PrP C on synaptic function and neuronal health are still not completely understood. Studies in yeast, mammalian cells, and mouse models support the hypothesis that PrP C plays a major role in neuroprotection and neuronal differentiation (for review, see Refs. 1-3).In humans, the initial cognitive dysfunction observed in transmissible spongiform encephalopathies is remarkably similar to those observed in Alzheimer disease (AD). Therefore, synaptic failure is likely to play a major role in the cognitive alterations seen in these neurological disorders (4). For instance, in AD, the role for A␤ ligands in synaptic dysfunction has received considerable attention (5, 6). Interestingly, recent work provided evidence that PrP C functions as a receptor for A␤ and that this interaction mediates some of the effects of A␤ oligomers in synaptic plasticity (7) although these results are controversial at the moment (8, 9). Moreover, PrP C seems to regulate the ␤-secretase cleavage of amyloid precursor protein, thereby regulating the production of A␤ (10). In addition, ␣-secretase regulates the cleavage of PrP C , generating an N-terminal fragment with neuroprotective activity (11,12)...

The Prion Protein Modulates A-type K+ Currents Mediated by Kv4.2 Complexes through Dipeptidyl Aminopeptidase-like Protein 6

“…In prior analyses, PrP C has been implicated in the modulation of a variety of ion channels, including GABA A receptor/ channels (5,6,8), calcium-dependent K ϩ channels, and NMDA receptors/channels (16, 17, 48, 56, 57); stress-inducible protein-1-dependent intracellular Ca 2ϩ fluxes mediated by the ␣7 nicotinic acetylcholine receptor (14,15,58); and an AMPA-dependent Zn 2ϩ reuptake phenomenon (59). Remarkably, these studies convey a diversity of mechanisms whereby PrP C modulates ion channels and neuronal excitability.…”

PRNP/prion protein regulates the secretion of exosomes modulating CAV1/caveolin-1-suppressed autophagy

“…3,4 PRNP cellular functions are attributed to its interaction with a set of protein complexes such as LAMA1/laminin-1-GRM/ metabotropic glutamate receptors and STIP1 (stress-induced phosphoprotein 1)-CHRNA7/a7 nicotinic acetylcholine receptors. [5][6][7] Some PRNP interactions take place in lipid raft microdomains such as those involving NCAM (neural cell adhesion molecule) and CAV1/caveolin-1, which couple PRNP to the tyrosine kinase FYN (Fyn proto-oncogene). 8,9 These complexes modulate neuroprotection against cellular and systemic insults, [10][11][12] participate in cell signaling cascades, 13 promote neuritogenesis, 14 regulate neuronal plasticity, excitability, memory formation, and consolidation, 15 and mediate synaptic vesicle transmission.…”

Uncontrolled SFK-mediated protein trafficking in prion and Alzheimer's disease

“…48,49 Accordingly, biochemical data from human tissue and cultured cells indicate that 356 E. M alaga-Trillo and K. Ochs PrP C interacts with the a7 and b4 nAChR subunits within macromolecular complexes. 50,51 Furthermore, when analyzing PrP function in zebrafish embryonic trunk motor neurons, we observed strong co-localization of activated SFKs, AChR and tyrosine phosphorylated NR2B NMDA receptor subunits at PrP-positive NMJs (K. Ochs and E M alaga-Trillo, in preparation). Upon PrP downregulation, the levels of activated SFKs and neuroreceptors at these postsynaptic sites decreased and their pattern of distribution became disrupted as motor axons failed to elongate and branch properly.…”