AIP limits neurotransmitter release by inhibiting calcium bursts from the ryanodine receptor

Nat Commun. 2017 Nov 9;8(1):1380. doi: 10.1038/s41467-017-01704-z.

Abstract

Pituitary tumors are frequently associated with mutations in the AIP gene and are sometimes associated with hypersecretion of growth hormone. It is unclear whether other factors besides an enlarged pituitary contribute to the hypersecretion. In a genetic screen for suppressors of reduced neurotransmitter release, we identified a mutation in Caenorhabditis elegans AIPR-1 (AIP-related-1), which causes profound increases in evoked and spontaneous neurotransmitter release, a high frequency of spontaneous calcium transients in motor neurons and an enlarged readily releasable pool of vesicles. Calcium bursts and hypersecretion are reversed by mutations in the ryanodine receptor but not in the voltage-gated calcium channel, indicating that these phenotypes are caused by a leaky ryanodine receptor. AIPR-1 is physically associated with the ryanodine receptor at synapses. Finally, the phenotypes in aipr-1 mutants can be rescued by presynaptic expression of mouse AIP, demonstrating that a conserved function of AIP proteins is to inhibit calcium release from ryanodine receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Calcium Signaling / physiology*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Motor Neurons / metabolism
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurotransmitter Agents / metabolism
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Synaptic Transmission / physiology

Substances

  • AIPR-1 protein, C elegans
  • Caenorhabditis elegans Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Neurotransmitter Agents
  • Ryanodine Receptor Calcium Release Channel
  • aryl hydrocarbon receptor-interacting protein