Store-Operated Calcium Entry through Orai Is Required for Transcriptional Maturation of the Flight Circuit in Drosophila

J Neurosci. 2015 Oct 7;35(40):13784-99. doi: 10.1523/JNEUROSCI.1680-15.2015.

Abstract

Store operated calcium entry (SOCE) is thought to primarily regulate calcium homeostasis in neurons. Subsequent to identification of Orai as the SOCE channel in nonexcitable cells, investigation of Orai function in neurons demonstrated a requirement for SOCE in Drosophila flight. Here, by analysis of an Orai mutant and by controlled expression of a dominant-negative Drosophila Orai transgene, we show that Orai-mediated SOCE is required in dopaminergic interneurons of the flight circuit during pupal development. Expression of dominant-negative Orai in dopaminergic neurons of pupae abolished flight. The loss of Orai-mediated SOCE alters transcriptional regulation of dopaminergic neurons, leading to downregulation of the enzyme tyrosine hydroxylase, which is essential for dopamine synthesis, and the dopamine transporter, which is required for dopamine uptake after synaptic release. These studies suggest that modulation of SOCE could serve as a novel mechanism for restoring dopamine levels in dopaminergic neurons.

Significance statement: The specificity of an animal's response to an environmental stimulus is determined in part by the release of neurotransmitters, which are sensed by responding neurons through cognate receptors on their surface. One way by which neurons respond is through release of calcium from intracellular stores followed by store refilling from extracellular calcium sources. This mechanism is called store-operated calcium entry (SOCE). The function of SOCE in neurons has been debated. Here we describe a new function for SOCE in the regulation of neurotransmitter levels in Drosophila flight neurons. This cell-signaling mechanism is required to maintain optimal levels of a key enzyme for dopamine synthesis and may serve as a mechanism for restoring dopamine levels in relevant pathological conditions.

Keywords: IP3R; STIM; dopamine transporter; dopaminergic neurons; tyrosine hydroxylase.

Publication types

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

MeSH terms

  • Acetyl-CoA Carboxylase / genetics
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Animals, Genetically Modified
  • Calcium / metabolism*
  • Calcium Signaling / genetics
  • Cells, Cultured
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopaminergic Neurons / metabolism
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Flight, Animal / physiology*
  • Flow Cytometry
  • Gene Expression Regulation, Developmental / genetics*
  • Larva
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mutation / genetics*
  • Neural Pathways / physiology
  • ORAI1 Protein
  • Pupa
  • Rats
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • DAT protein, Drosophila
  • Dopamine Plasma Membrane Transport Proteins
  • Drosophila Proteins
  • Membrane Proteins
  • ORAI1 Protein
  • olf186-F protein, Drosophila
  • Tyrosine 3-Monooxygenase
  • Acetyl-CoA Carboxylase
  • Calcium