title: Neuropeptide secreted from a pacemaker activates neurons to control a rhythmic behavior.
abstract: BACKGROUND
  Rhythmic behaviors are driven by endogenous biological clocks in pacemakers, which must reliably transmit timing information to target tissues that execute rhythmic outputs. During the defecation motor program in C. elegans, calcium oscillations in the pacemaker (intestine), which occur about every 50 s, trigger rhythmic enteric muscle contractions through downstream GABAergic neurons that innervate enteric muscles. However, the identity of the timing signal released by the pacemaker and the mechanism underlying the delivery of timing information to the GABAergic neurons are unknown.
  
  
  RESULTS
  Here, we show that a neuropeptide-like protein (NLP-40) released by the pacemaker triggers a single rapid calcium transient in the GABAergic neurons during each defecation cycle. We find that mutants lacking nlp-40 have normal pacemaker function, but lack enteric muscle contractions. NLP-40 undergoes calcium-dependent release that is mediated by the calcium sensor, SNT-2/synaptotagmin. We identify AEX-2, the G-protein-coupled receptor on the GABAergic neurons, as the receptor for NLP-40. Functional calcium imaging reveals that NLP-40 and AEX-2/GPCR are both necessary for rhythmic activation of these neurons. Furthermore, acute application of synthetic NLP-40-derived peptide depolarizes the GABAergic neurons in vivo.
  
  
  CONCLUSIONS
  Our results show that NLP-40 carries the timing information from the pacemaker via calcium-dependent release and delivers it to the GABAergic neurons by instructing their activation. Thus, we propose that rhythmic release of neuropeptides can deliver temporal information from pacemakers to downstream neurons to execute rhythmic behaviors.
authors.affiliation: Graduate Program in Genetic, Molecular and Cellular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.forename: Kelly
authors.initials: K
authors.lastname: Girskis
authors.forename: Tom
authors.initials: T
authors.lastname: Janssen
authors.forename: Jason P
authors.initials: JP
authors.lastname: Chan
authors.forename: Krishnakali
authors.initials: K
authors.lastname: Dasgupta
authors.forename: James A
authors.initials: JA
authors.lastname: Knowles
authors.forename: Liliane
authors.initials: L
authors.lastname: Schoofs
authors.forename: Derek
authors.initials: D
authors.lastname: Sieburth
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D003672:Defecation; D007422:Intestines / Q000502:physiology; D008969:Molecular Sequence Data; D009119:Muscle Contraction; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D050861:Synaptotagmin II / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; C584219:NLP-40 protein, C elegans; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; D050861:Synaptotagmin II; D002118:Calcium