Protein Kinase A Activation Promotes Plasma Membrane Insertion of DCC from an Intracellular Pool: A Novel Mechanism Regulating Commissural Axon Extension

The Journal of Neuroscience, 2004 · DOI: 10.1523/JNEUROSCI.4934-03.2004 · Published: March 24, 2004

Regenerative Medicine Neurology Genetics

Simple Explanation

This study investigates how protein kinase A (PKA) affects axon growth, focusing on the DCC receptor's role in netrin-1 signaling. DCC, a receptor for netrin-1, exists both on the cell surface and within intracellular vesicles in developing spinal neurons. Activating PKA enhances the movement of DCC to the cell surface, increasing axon extension in response to netrin-1, suggesting a novel regulatory mechanism.

Study Duration

Not specified

Participants

Embryonic rat spinal commissural neurons

Evidence Level

In vitro and ex vivo experiments

Key Findings

1
Netrin-1 modestly increases cell surface DCC without activating PKA, suggesting a PKA-independent mechanism.
2
PKA activation potentiates netrin-1-dependent DCC insertion into the plasma membrane, enhancing axon outgrowth.
3
Inhibition of adenylate cyclase, PKA, or exocytosis blocks PKA-induced DCC translocation, indicating mobilization from an intracellular store.

Research Summary

The study reveals that DCC, a netrin-1 receptor, is present both on the neuronal surface and in intracellular pools in embryonic rat spinal commissural neurons. Netrin-1 application leads to a modest increase in cell surface DCC, while PKA activation enhances netrin-1-dependent DCC mobilization and axon outgrowth. PKA-dependent DCC translocation to the plasma membrane is selective and requires exocytosis, highlighting a novel mechanism regulating axon extension.

Practical Implications

Targeted Therapies

Understanding PKA's role in DCC trafficking could lead to targeted therapies for promoting axon regeneration after spinal cord injury.

Drug Development

Identifying molecules that enhance or inhibit PKA-dependent DCC mobilization could offer new avenues for drug development in neurodevelopmental disorders.

Cellular Mechanisms

This research provides insights into the cellular mechanisms regulating receptor presentation and axon guidance, contributing to a broader understanding of neural development.

Study Limitations

1
The study is primarily in vitro, limiting direct translation to in vivo conditions.
2
The precise mechanisms of DCC vesicle trafficking and specificity remain to be fully elucidated.
3
The study focuses on embryonic rat spinal neurons, and findings may not be generalizable to all neuronal types or species.

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