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Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1

Natasha M Sosanya1, Peggy P C Huang, Luisa P Cacheaux

  • 1Center for Learning and Memory, Section of Neurobiology, University of Texas at Austin, Austin, TX 78712, USA.

The Journal of Cell Biology
|July 10, 2013
PubMed

Insights

This study reveals how neuron excitability changes by regulating Kv1.1 ion channel expression. It uncovers a novel mechanism involving mTORC1 kinase, miR-129, and HuD protein controlling Kv1.1 mRNA translation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Neuronal intrinsic excitability is crucial for brain function.
  • Mechanisms of activity-dependent regulation of ion channel expression remain largely unknown.
  • The role of mTORC1 signaling in neuronal plasticity is increasingly recognized.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying site-specific changes in intrinsic excitability.
  • To investigate the regulation of voltage-gated potassium channel Kv1.1 mRNA translation.
  • To identify key regulatory factors involved in neuronal activity-dependent plasticity.

Main Methods:

  • Investigated the interaction between mTORC1 kinase, miR-129, and HuD protein.
  • Analyzed the translational regulation of Kv1.1 mRNA.
  • Studied the impact of mTORC1 inhibition on mRNA stability and protein binding.

Main Results:

  • mTORC1 kinase activity inversely regulates Kv1.1 mRNA translation via miR-129 and HuD.
  • miR-129 represses Kv1.1 mRNA translation when mTORC1 is active.
  • HuD protein promotes Kv1.1 mRNA translation when mTORC1 is inactive.
  • mTORC1 inhibition leads to degradation of HuD target mRNAs, freeing HuD to bind Kv1.1 mRNA.

Conclusions:

  • mTORC1 signaling regulates neuronal excitability through bidirectional control of Kv1.1 ion channel expression.
  • mRNA stability and HuD-dependent translation are key mediators of this regulation.
  • This provides a novel mechanism for activity-dependent neuronal plasticity.

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