title: A novel CaM kinase II pathway controls the location of neuropeptide release from Caenorhabditis elegans motor neurons.
abstract: Neurons release neuropeptides via the regulated exocytosis of dense core vesicles (DCVs) to evoke or modulate behaviors. We found that Caenorhabditis elegans motor neurons send most of their DCVs to axons, leaving very few in the cell somas. How neurons maintain this skewed distribution and the extent to which it can be altered to control DCV numbers in axons or to drive release from somas for different behavioral impacts is unknown. Using a forward genetic screen, we identified loss-of-function mutations in UNC-43 (CaM kinase II) that reduce axonal DCV levels by ∼90% and cell soma/dendrite DCV levels by ∼80%, leaving small synaptic vesicles largely unaffected. Blocking regulated secretion in unc-43 mutants restored near wild-type axonal levels of DCVs. Time-lapse video microscopy showed no role for CaM kinase II in the transport of DCVs from cell somas to axons. In vivo secretion assays revealed that much of the missing neuropeptide in unc-43 mutants is secreted via a regulated secretory pathway requiring UNC-31 (CAPS) and UNC-18 (nSec1). DCV cargo levels in unc-43 mutants are similarly low in cell somas and the axon initial segment, indicating that the secretion occurs prior to axonal transport. Genetic pathway analysis suggests that abnormal neuropeptide function contributes to the sluggish basal locomotion rate of unc-43 mutants. These results reveal a novel pathway controlling the location of DCV exocytosis and describe a major new function for CaM kinase II.
authors.affiliation: Genetic Models of Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hoover
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Edwards
authors.forename: Szi-chieh
authors.initials: SC
authors.lastname: Yu
authors.forename: Maike
authors.initials: M
authors.lastname: Kittelmann
authors.forename: Janet E
authors.initials: JE
authors.lastname: Richmond
authors.forename: Stefan
authors.initials: S
authors.lastname: Eimer
authors.forename: Rosalina M
authors.initials: RM
authors.lastname: Yorks
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Miller
mesh_terms: D000818:Animals; D001369:Axons / Q000000981:diagnostic imaging / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D018389:Codon, Nonsense; D003712:Dendrites / Q000000981:diagnostic imaging / Q000378:metabolism; D005089:Exocytosis; D008854:Microscopy, Electron; D009046:Motor Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009479:Neuropeptides / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport; D022142:Secretory Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D014463:Ultrasonography; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; D018389:Codon, Nonsense; D009479:Neuropeptides; D010750:Phosphoproteins; C107581:UNC-31 protein, C elegans; C082636:Unc-18 protein, C elegans; D033921:Vesicular Transport Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517679:unc-43 protein, C elegans
keywords: C. elegans; CaM Kinase II; Dense core vesicle; Neuropeptide release; Regulated secretion; placeholder