title: Macoilin, a conserved nervous system-specific ER membrane protein that regulates neuronal excitability.
abstract: 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.
authors: Medical Research Council-Laboratory of Molecular Biology, Cambridge, UK.
authors: Fausto
authors: F
authors: Arellano-Carbajal
authors: Luis
authors: L
authors: Briseño-Roa
authors: Africa
authors: A
authors: Couto
authors: Benny H H
authors: BH
authors: Cheung
authors: Michel
authors: M
authors: Labouesse
authors: Mario
authors: M
authors: de Bono
mesh_terms: D000448:Aldicarb / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology; D001369:Axons / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D017173:Caenorhabditis elegans / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism; D007978:Levamisole / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010802:Phylogeny; D016415:Sequence Alignment; D013569:Synapses / Q000378:metabolism
chemical_list: D000969:Antinematodal Agents; D029742:Caenorhabditis elegans Proteins; D007473:Ion Channels; D008565:Membrane Proteins; C559590:maco-1 protein, C elegans; D007978:Levamisole; D000448:Aldicarb; D002118:Calcium