Home LiteratureArticle Details
PMID: 12657671 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The EGL-21 carboxypeptidase E facilitates acetylcholine release at Caenorhabditis elegans neuromuscular junctions.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 23 ·No. 6 ·2003-03-15 ·Pages 2122-30

Jacob TC, Kaplan JM

Abstract

Proneuropeptides are packaged into dense-core vesicles in which they are processed into active peptides by copackaged enzymes. Proprotein convertases (PCs) cleave precursors after dibasic residues, and carboxypeptidases remove basic residues from the C terminals. We show here that the Caenorhabditis elegans egl-21 gene encodes a protein that is very similar to carboxypeptidase E (CPE) and is broadly expressed in the nervous system. Mutants lacking either egl-21 CPE or egl-3, which encodes the C. elegans ortholog of PC type 2 (PC2), were defective for processing endogenously expressed FMRFamide (Phe-Met-Arg-Phe-NH2)-related peptides (FaRPs). Mutants lacking the unc-104 kinesin motor protein were defective for anterograde movement of dense-core vesicle components, including egl-3 PC2, egl-21 CPE, and FaRPs. We provide evidence that egl-3 PC2 and egl-21 CPE mutants have diminished acetylcholine release at neuromuscular junctions (NMJs). Taken together, these results suggest that egl-21 CPE and egl-3 PC2 process endogenous neuropeptides that facilitate acetylcholine release at C. elegans NMJs.

MeSH Terms
Acetylcholine/metabolism Amino Acid Sequence Animals Biological Transport/physiology Caenorhabditis elegans Caenorhabditis elegans Proteins/genetics,metabolism Carboxypeptidase H Carboxypeptidases/genetics,metabolism Cloning, Molecular FMRFamide/metabolism Humans Mice Molecular Sequence Data Motor Activity/physiology Mutation Nerve Tissue Proteins/metabolism Nervous System/metabolism Neuromuscular Junction/metabolism Neuropeptides/metabolism Organ Specificity Proprotein Convertase 2 Protein Processing, Post-Translational Secretory Vesicles/metabolism Sequence Alignment Subtilisins/metabolism
Chemicals
Caenorhabditis elegans Proteins Nerve Tissue Proteins Neuropeptides UNC-104 protein, C elegans FMRFamide Carboxypeptidases Carboxypeptidase H Subtilisins EGL-3 proprotein convertase, C elegans Proprotein Convertase 2 Acetylcholine
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Jacob Tija C
Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720, USA.
Kaplan Joshua M
References (74)
74 references, click to expand
  1. The neuroendocrine protein 7B2 is required for peptide hormone processing in vivo and provides a novel mechanism for pituitary Cushing's disease.
    Cell. 1999 Mar 5;96(5):689-700 PMID: 10089884
  2. The complete family of genes encoding G proteins of Caenorhabditis elegans.
    Nat Genet. 1999 Apr;21(4):414-9 PMID: 10192394
  3. Glu300 of rat carboxypeptidase E is essential for enzymatic activity but not substrate binding or routing to the regulated secretory pathway.
    J Biol Chem. 1999 Apr 23;274(17):11582-6 PMID: 10206965
  4. A role for amontillado, the Drosophila homolog of the neuropeptide precursor processing protease PC2, in triggering hatching behavior.
    J Neurosci. 1999 Aug 15;19(16):6942-54 PMID: 10436051
  5. Visualization of synaptic specializations in live C. elegans with synaptic vesicle protein-GFP fusions.
    J Neurosci Methods. 1999 Jul 1;89(1):33-40 PMID: 10476681
  6. Goalpha and diacylglycerol kinase negatively regulate the Gqalpha pathway in C. elegans.
    Neuron. 1999 Oct;24(2):323-33 PMID: 10571227
  7. Facilitation of synaptic transmission by EGL-30 Gqalpha and EGL-8 PLCbeta: DAG binding to UNC-13 is required to stimulate acetylcholine release.
    Neuron. 1999 Oct;24(2):335-46 PMID: 10571228
  8. FMRFamide-related neuropeptide gene family in Caenorhabditis elegans.
    Brain Res. 1999 Nov 27;848(1-2):26-34 PMID: 10612695
  9. A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila.
    Cell. 1999 Dec 23;99(7):791-802 PMID: 10619432
  10. Neuropeptide gene families in the nematode Caenorhabditis elegans.
    Ann N Y Acad Sci. 1999;897:239-52 PMID: 10676452
  11. Serotonin inhibition of synaptic transmission: Galpha(0) decreases the abundance of UNC-13 at release sites.
    Neuron. 1999 Sep;24(1):231-42 PMID: 10677040
  12. A look at the Caenorhabditis elegans Kex2/Subtilisin-like proprotein convertase family.
    Bioessays. 2000 Jun;22(6):545-53 PMID: 10842308
  13. Molecular cloning and characterization of a new insulin/IGF-like peptide of the nematode Caenorhabditis elegans.
    Biochem Biophys Res Commun. 2000 Jul 5;273(2):431-6 PMID: 10873623
  14. PHM is required for normal developmental transitions and for biosynthesis of secretory peptides in Drosophila.
    Dev Biol. 2000 Oct 1;226(1):118-36 PMID: 10993678
  15. Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family.
    Genes Dev. 2001 Mar 15;15(6):672-86 PMID: 11274053
  16. Attenuated processing of proglucagon and glucagon-like peptide-1 in carboxypeptidase E-deficient mice.
    J Endocrinol. 2001 Jun;169(3):595-602 PMID: 11375130
  17. Identification of peptides from brain and pituitary of Cpe(fat)/Cpe(fat) mice.
    Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9971-6 PMID: 11481435
  18. Drosophila CAPS is an essential gene that regulates dense-core vesicle release and synaptic vesicle fusion.
    Neuron. 2001 Aug 16;31(3):421-37 PMID: 11516399
  19. Multiple amidated neuropeptides are required for normal circadian locomotor rhythms in Drosophila.
    J Neurosci. 2001 Sep 1;21(17):6673-86 PMID: 11517257
  20. Isolation and preliminary biological assessment of AADGAPLIRFamide and SVPGVLRFamide from Caenorhabditis elegans.
    Biochem Biophys Res Commun. 2001 Sep 7;286(5):1170-6 PMID: 11527423
  21. The EGL-3 proprotein convertase regulates mechanosensory responses of Caenorhabditis elegans.
    J Neurosci. 2001 Dec 1;21(23):9265-72 PMID: 11717360
  22. Identification of neuropeptide-like protein gene families in Caenorhabditiselegans and other species.
    Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14000-5 PMID: 11717458
  23. Regulation of the pharynx of Caenorhabditis elegans by 5-HT, octopamine, and FMRFamide-like neuropeptides.
    J Neurobiol. 2001 Nov 15;49(3):235-44 PMID: 11745661
  24. Regulation of retrograde signaling at neuromuscular junctions by the novel C2 domain protein AEX-1.
    Neuron. 2002 Jan 17;33(2):249-59 PMID: 11804572
  25. Egg-laying defective mutants of the nematode Caenorhabditis elegans.
    Genetics. 1983 Aug;104(4):619-47 PMID: 11813735
  26. Functional characterization of the adenylyl cyclase gene sgs-1 by analysis of a mutational spectrum in Caenorhabditis elegans.
    Genetics. 2002 May;161(1):133-42 PMID: 12019229
  27. Ubiquitin and AP180 regulate the abundance of GLR-1 glutamate receptors at postsynaptic elements in C. elegans.
    Neuron. 2002 Jul 3;35(1):107-20 PMID: 12123612
  28. Localization of FMRFamide-like peptides in Caenorhabditis elegans.
    J Comp Neurol. 1992 Feb 8;316(2):251-60 PMID: 1573054
  29. Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans.
    Cell. 1991 May 31;65(5):837-47 PMID: 1710172
  30. Mutations in the bli-4 (I) locus of Caenorhabditis elegans disrupt both adult cuticle and early larval development.
    Genetics. 1991 Sep;129(1):95-102 PMID: 1936966
  31. Two soluble forms of bovine carboxypeptidase H have different NH2-terminal sequences.
    J Biol Chem. 1990 Oct 5;265(28):17101-5 PMID: 2211611
  32. Identification of the pH-dependent membrane anchor of carboxypeptidase E (EC 3.4.17.10).
    J Biol Chem. 1990 Feb 15;265(5):2476-82 PMID: 2303412
  33. Human carboxypeptidase E. Isolation and characterization of the cDNA, sequence conservation, expression and processing in vitro.
    Biochem J. 1990 Apr 15;267(2):517-25 PMID: 2334405
  34. Organogenesis in C. elegans: positioning of neurons and muscles in the egg-laying system.
    Neuron. 1990 May;4(5):681-95 PMID: 2344407
  35. The action of FMRFamide (Phe-Met-Arg-Phe-NH2) and related peptides on mammals.
    Peptides. 1988 Jul-Aug;9(4):915-22 PMID: 3067224
  36. Distribution and partial characterization of FMRFamide-like peptides in the stomatogastric nervous systems of the rock crab, Cancer borealis, and the spiny lobster, Panulirus interruptus.
    J Comp Neurol. 1987 May 1;259(1):150-63 PMID: 3584554
  37. The genetics of Caenorhabditis elegans.
    Genetics. 1974 May;77(1):71-94 PMID: 4366476
  38. Caenorhabditis elegans mutants resistant to inhibitors of acetylcholinesterase.
    Genetics. 1995 Jun;140(2):527-35 PMID: 7498734
  39. The silver gene of Drosophila melanogaster encodes multiple carboxypeptidases similar to mammalian prohormone-processing enzymes.
    Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9470-4 PMID: 7568156
  40. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity.
    Nat Genet. 1995 Jun;10(2):135-42 PMID: 7663508
  41. A neuropeptide gene defined by the Drosophila memory mutant amnesiac.
    Science. 1995 May 12;268(5212):869-73 PMID: 7754370
  42. The bli-4 locus of Caenorhabditis elegans encodes structurally distinct kex2/subtilisin-like endoproteases essential for early development and adult morphology.
    Genes Dev. 1995 Apr 15;9(8):956-71 PMID: 7774813
  43. Modulation of serotonin-controlled behaviors by Go in Caenorhabditis elegans.
    Science. 1995 Mar 17;267(5204):1648-51 PMID: 7886454
  44. Participation of the protein Go in multiple aspects of behavior in C. elegans.
    Science. 1995 Mar 17;267(5204):1652-5 PMID: 7886455
  45. Synaptic function is impaired but not eliminated in C. elegans mutants lacking synaptotagmin.
    Cell. 1993 Jul 2;73(7):1291-305 PMID: 8391930
  46. The C-terminal region of carboxypeptidase E involved in membrane binding is distinct from the region involved with intracellular routing.
    J Biol Chem. 1996 Mar 15;271(11):6077-83 PMID: 8626393
  47. Mutations in a C. elegans Gqalpha gene disrupt movement, egg laying, and viability.
    Neuron. 1996 May;16(5):999-1009 PMID: 8630258
  48. Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice.
    Endocrinology. 1996 Jul;137(7):2954-8 PMID: 8770919
  49. A genetic selection for Caenorhabditis elegans synaptic transmission mutants.
    Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12593-8 PMID: 8901627
  50. Carboxypeptidase E activity is deficient in mice with the fat mutation. Effect on peptide processing.
    J Biol Chem. 1996 Nov 29;271(48):30619-24 PMID: 8940036
  51. APEASPFIRFamide, a novel FMRFamide-related decapeptide from Caenorhabditis elegans: structure and myoactivity.
    Biochem Biophys Res Commun. 1997 Feb 24;231(3):591-5 PMID: 9070852
  52. Effect of carboxypeptidase E deficiency on progastrin processing and gastrin messenger ribonucleic acid expression in mice with the fat mutation.
    Endocrinology. 1997 May;138(5):1959-63 PMID: 9112393
  53. The pro region is not required for the expression or intracellular routeing of carboxypeptidase E.
    Biochem J. 1997 Apr 1;323 ( Pt 1):265-71 PMID: 9173892
  54. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2.
    Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6646-51 PMID: 9192619
  55. An activating mutation in a Caenorhabditis elegans Gs protein induces neural degeneration.
    Genes Dev. 1997 Jun 15;11(12):1493-503 PMID: 9203577
  56. Cholecystokinin (CCK) levels are greatly reduced in the brains but not the duodenums of Cpe(fat)/Cpe(fat) mice: a regional difference in the involvement of carboxypeptidase E (Cpe) in pro-CCK processing.
    Endocrinology. 1997 Sep;138(9):4034-7 PMID: 9275097
  57. Caenorhabditis elegans rab-3 mutant synapses exhibit impaired function and are partially depleted of vesicles.
    J Neurosci. 1997 Nov 1;17(21):8061-73 PMID: 9334382
  58. Disturbed progastrin processing in carboxypeptidase E-deficient fat mice.
    FEBS Lett. 1997 Oct 13;416(1):45-50 PMID: 9369230
  59. Inhibitory effects of nematode FMRFamide-related peptides (FaRPs) on muscle strips from Ascaris suum.
    Invert Neurosci. 1995 Dec;1(3):255-65 PMID: 9372147
  60. The G alpha protein ODR-3 mediates olfactory and nociceptive function and controls cilium morphogenesis in C. elegans olfactory neurons.
    Neuron. 1998 Jan;20(1):55-67 PMID: 9459442
  61. G alphas-induced neurodegeneration in Caenorhabditis elegans.
    J Neurosci. 1998 Apr 15;18(8):2871-80 PMID: 9526004
  62. Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
    J Cell Biol. 1998 Apr 20;141(2):431-41 PMID: 9548721
  63. New insulin-like proteins with atypical disulfide bond pattern characterized in Caenorhabditis elegans by comparative sequence analysis and homology modeling.
    Genome Res. 1998 Apr;8(4):348-53 PMID: 9548970
  64. Ethanol intoxication in Drosophila: Genetic and pharmacological evidence for regulation by the cAMP signaling pathway.
    Cell. 1998 Jun 12;93(6):997-1007 PMID: 9635429
  65. KSAYMRFamide (PF3/AF8) is present in the free-living nematode, Caenorhabditis elegans.
    Biochem Biophys Res Commun. 1998 Jul 20;248(2):422-5 PMID: 9675153
  66. Differential regulation of exocytosis by calcium and CAPS in semi-intact synaptosomes.
    Neuron. 1998 Jul;21(1):147-54 PMID: 9697859
  67. Cloning and developmental regulation of a novel member of the insulin-like gene family in Caenorhabditis elegans.
    Biochem Biophys Res Commun. 1998 Aug 19;249(2):385-90 PMID: 9712706
  68. G protein hyperactivation of the Caenorhabditis elegans adenylyl cyclase SGS-1 induces neuronal degeneration.
    EMBO J. 1998 Sep 1;17(17):5059-65 PMID: 9724641
  69. Disruption of a neuropeptide gene, flp-1, causes multiple behavioral defects in Caenorhabditis elegans.
    Science. 1998 Sep 11;281(5383):1686-90 PMID: 9733518
  70. Functional redundancy of FMRFamide-related peptides at the Drosophila larval neuromuscular junction.
    J Neurosci. 1998 Sep 15;18(18):7138-51 PMID: 9736637
  71. Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans.
    Cell. 1998 Sep 4;94(5):679-89 PMID: 9741632
  72. Altered processing of procholecystokinin in carboxypeptidase E-deficient fat mice: differential synthesis in neurons and endocrine cells.
    FEBS Lett. 1998 Sep 25;436(1):61-6 PMID: 9771894
  73. Neurobiology of the Caenorhabditis elegans genome.
    Science. 1998 Dec 11;282(5396):2028-33 PMID: 9851919
  74. Isolation, pharmacology and gene organization of KPSFVRFamide: a neuropeptide from Caenorhabditis elegans.
    Biochem Biophys Res Commun. 1999 Jan 8;254(1):222-30 PMID: 9920762
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2003-03-15
Pages
2122-30
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6742027
Subset
IM
Grants
NINDS NIH HHS · R01 NS032196 · United States
NINDS NIH HHS · R37 NS032196 · United States
NINDS NIH HHS · NS32196 · United States
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2