Macoilin, a conserved nervous system-specific ER membrane protein that regulates neuronal excitability

PLoS Genet. 2011 Mar;7(3):e1001341. doi: 10.1371/journal.pgen.1001341. Epub 2011 Mar 17.


Genome sequence comparisons have highlighted many novel gene families that are conserved across animal phyla but whose biological function is unknown. Here, we functionally characterize a member of one such family, the macoilins. Macoilins are characterized by several highly conserved predicted transmembrane domains towards the N-terminus and by coiled-coil regions C-terminally. They are found throughout Eumetazoa but not in other organisms. Mutants for the single Caenorhabditis elegans macoilin, maco-1, exhibit a constellation of behavioral phenotypes, including defects in aggregation, O₂ responses, and swimming. MACO-1 protein is expressed broadly and specifically in the nervous system and localizes to the rough endoplasmic reticulum; it is excluded from dendrites and axons. Apart from subtle synapse defects, nervous system development appears wild-type in maco-1 mutants. However, maco-1 animals are resistant to the cholinesterase inhibitor aldicarb and sensitive to levamisole, suggesting pre-synaptic defects. Using in vivo imaging, we show that macoilin is required to evoke Ca²(+) transients, at least in some neurons: in maco-1 mutants the O₂-sensing neuron PQR is unable to generate a Ca²(+) response to a rise in O₂. By genetically disrupting neurotransmission, we show that pre-synaptic input is not necessary for PQR to respond to O₂, indicating that the response is mediated by cell-intrinsic sensory transduction and amplification. Disrupting the sodium leak channels NCA-1/NCA-2, or the N-,P/Q,R-type voltage-gated Ca²(+) channels, also fails to disrupt Ca²(+) responses in the PQR cell body to O₂ stimuli. By contrast, mutations in egl-19, which encodes the only Caenorhabditis elegans L-type voltage-gated Ca²(+) channel α1 subunit, recapitulate the Ca²(+) response defect we see in maco-1 mutants, although we do not see defects in localization of EGL-19. Together, our data suggest that macoilin acts in the ER to regulate assembly or traffic of ion channels or ion channel regulators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldicarb / pharmacology
  • Amino Acid Sequence
  • Animals
  • Antinematodal Agents / pharmacology
  • Axons / metabolism
  • Behavior, Animal / physiology
  • Caenorhabditis elegans / classification
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism*
  • Calcium / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Ion Channels / metabolism
  • Levamisole / pharmacology
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Mutation / genetics
  • Neurons / cytology
  • Neurons / metabolism*
  • Phylogeny
  • Sequence Alignment
  • Synapses / metabolism


  • Antinematodal Agents
  • Caenorhabditis elegans Proteins
  • Ion Channels
  • Membrane Proteins
  • maco-1 protein, C elegans
  • Levamisole
  • Aldicarb
  • Calcium