A presynaptic ENaC channel drives homeostatic plasticity

Neuron. 2013 Sep 18;79(6):1183-96. doi: 10.1016/j.neuron.2013.06.048. Epub 2013 Aug 22.

Abstract

An electrophysiology-based forward genetic screen has identified two genes, pickpocket11 (ppk11) and pickpocket16 (ppk16), as being necessary for the homeostatic modulation of presynaptic neurotransmitter release at the Drosophila neuromuscular junction (NMJ). Pickpocket genes encode Degenerin/Epithelial Sodium channel subunits (DEG/ENaC). We demonstrate that ppk11 and ppk16 are necessary in presynaptic motoneurons for both the acute induction and long-term maintenance of synaptic homeostasis. We show that ppk11 and ppk16 are cotranscribed as a single mRNA that is upregulated during homeostatic plasticity. Acute pharmacological inhibition of a PPK11- and PPK16-containing channel abolishes the expression of short- and long-term homeostatic plasticity without altering baseline presynaptic neurotransmitter release, indicating remarkable specificity for homeostatic plasticity rather than NMJ development. Finally, presynaptic calcium imaging experiments support a model in which a PPK11- and PPK16-containing DEG/ENaC channel modulates presynaptic membrane voltage and, thereby, controls calcium channel activity to homeostatically regulate neurotransmitter release.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amiloride / analogs & derivatives
  • Amiloride / pharmacology
  • Animals
  • Animals, Genetically Modified
  • Calcium / metabolism
  • Central Nervous System / physiology*
  • Dose-Response Relationship, Drug
  • Drosophila Proteins / genetics
  • Drosophila melanogaster
  • Epithelial Sodium Channels / genetics
  • Epithelial Sodium Channels / metabolism*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Homeostasis / genetics
  • Homeostasis / physiology*
  • Larva
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuromuscular Junction / cytology
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / genetics
  • Neuromuscular Junction / physiology*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology*
  • Neuroprotective Agents / pharmacology
  • Nicotinic Antagonists / pharmacology
  • Patch-Clamp Techniques
  • Polyamines / pharmacology
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / physiology*
  • Sodium Channels / genetics

Substances

  • Drosophila Proteins
  • Epithelial Sodium Channels
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Nicotinic Antagonists
  • Polyamines
  • Sodium Channels
  • ppk protein, Drosophila
  • benzamil
  • delta-philanthotoxin
  • Amiloride
  • Calcium
  • ethylisopropylamiloride