NMDA Receptor and L-Type Calcium Channel Modulate Prion Formation

Area of Science:

• Neuroscience
• Molecular Biology
• Prion Disease Research

Background:

• Transmissible neurodegenerative prion diseases result from the misfolding of cellular prion protein (PrPC) into infectious prions (PrPSc).
• Efficient prion formation relies on intact cellular functions, with neurons being primary targets.
• Synaptic plasticity, a key neuronal function, was investigated as a potential modulator of PrPSc formation.

Purpose of the Study:

• To investigate whether synaptic plasticity mechanisms influence the formation of misfolded prion protein isoforms (PrPSc).
• To explore the role of L-type calcium channels (LTCCs) and NMDA receptors (NMDARs) in modulating PrPSc levels.
• To elucidate the involvement of ERK signaling pathways in the relationship between synaptic plasticity and prion formation.

Main Methods:

• Immortalized gonadotropin-releasing hormone cells infected with the Rocky Mountain Laboratory prion strain were utilized.
• Cells were treated with agonists and antagonists of LTCCs and NMDARs.
• Western blotting was employed to assess PrPSc levels and phosphorylated ERK (pERK) signaling.

Main Results:

• Infected cells exhibited elevated pERK levels compared to uninfected controls.
• LTCC stimulation (Bay K8644) increased both pERK and PrPSc levels.
• Combined LTCC and NMDAR inhibition, or MK-801 (NMDAR blocker) treatment, reduced pERK and PrPSc levels, indicating modulation via these pathways.

Conclusions:

• Modulation of LTCC and NMDAR activity influences PrPSc formation through ERK signaling.
• Contrasting intracellular signals generated during synaptic plasticity, such as ERK and p38-JNK pathways, can impact prion conversion dynamics.
• These findings suggest a link between the complex signaling events of synaptic plasticity and the temporal progression of prion diseases.