Amyloid precursor protein enhances Nav1.6 sodium channel cell surface expression

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• The physiological function of Amyloid precursor protein (APP) is largely unknown, despite its association with Alzheimer's disease.
• Nav1.6 is crucial for regulating neuronal excitability in vivo.
• Shared phenotypes between APP and Nav1.6 gain/loss of function models suggest a potential interaction.

Purpose of the Study:

• To investigate the potential role of APP in modulating Nav1.6 sodium channel activity.
• To elucidate the molecular mechanisms underlying the interaction between APP and Nav1.6.

Main Methods:

• Co-localization and interaction studies of APP and Nav1.6 in mouse cortical neurons.
• APP knockdown experiments to assess effects on Nav1.6 currents and cell surface expression.
• G protein signaling pathway analysis using constitutively active and dominant-negative mutants.
• JNK pathway activity assessment and inhibition experiments.
• Site-directed mutagenesis of APP (Thr-668 phosphorylation) to study its impact on Nav1.6 interaction.

Main Results:

• APP was found to colocalize and interact with Nav1.6 in mouse cortical neurons.
• APP knockdown reduced Nav1.6 sodium channel currents and cell surface expression.
• APP-mediated increases in Nav1.6 cell surface expression were dependent on G protein signaling and JNK activity.
• Phosphorylation of APP at Thr-668 enhanced its interaction with Nav1.6, increasing channel surface expression.

Conclusions:

• APP enhances Nav1.6 sodium channel cell surface expression.
• This regulation occurs via a G protein-coupled JNK pathway.
• APP phosphorylation at Thr-668 is critical for its interaction with Nav1.6 and subsequent modulation of sodium channel expression.