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PMID: 19160073 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

The Ca(2+)-dependent activator protein for secretion CAPS: do I dock or do I prime?

Molecular neurobiology ·Vol. 39 ·No. 1 ·2009-02-00 ·Pages 62-72

Stevens DR, Rettig J

Abstract

The "Ca(2+)-dependent activator protein for secretion" (CAPS) is a protein which reconstitutes regulated secretion in permeabilized neuroendocrine cells. It is generally accepted that CAPS plays an important role in the release of the contents of dense core vesicles in the nervous system as well as in a variety of other secretory tissues. At which step in the exocytotic process CAPS functions as well as its role in the fusion of synaptic vesicles is still under dispute. A recent growth spurt in the CAPS field has been fueled by genetic approaches in Caenorhabditis elegans and Drosophila as well as the application of knockout and knockdown approaches in mouse cells and in cell lines, respectively. We have attempted to review the body of work that established CAPS as an important regulator of secretion and to describe new information that has furthered our understanding of how CAPS may function. We discuss the conclusions, point out areas where controversy remains, and suggest directions for future experiments.

MeSH Terms
Animals Brain/metabolism Calcium/metabolism Calcium-Binding Proteins/chemistry,metabolism Exocytosis/physiology Synaptic Vesicles/metabolism
Chemicals
Calcium-Binding Proteins Calcium
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Stevens David R
Physiologisches Institut, Universität des Saarlandes, Gebäude 59, Kirrberger Str. 8, 66421, Homburg/Saar, Germany.
Rettig Jens
References (69)
69 references, click to expand
  1. Severe sensory and sympathetic deficits in mice lacking neurotrophin-3.
    Nature. 1994 Jun 23;369(6482):658-61 PMID: 8208292
  2. Phosphatidylinositol 4,5-bisphosphate regulates SNARE-dependent membrane fusion.
    J Cell Biol. 2008 Jul 28;182(2):355-66 PMID: 18644890
  3. Identification of the minimal protein domain required for priming activity of Munc13-1.
    Curr Biol. 2005 Dec 20;15(24):2243-8 PMID: 16271475
  4. Excitatory and inhibitory autaptic currents in isolated hippocampal neurons maintained in cell culture.
    Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7834-8 PMID: 1679238
  5. Rapid regulated dense-core vesicle exocytosis requires the CAPS protein.
    Proc Natl Acad Sci U S A. 2000 May 9;97(10):5627-32 PMID: 10792045
  6. PKC-1 regulates secretion of neuropeptides.
    Nat Neurosci. 2007 Jan;10(1):49-57 PMID: 17128266
  7. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming.
    Neuron. 2001 Apr;30(1):183-96 PMID: 11343654
  8. Munc13-1 acts as a priming factor for large dense-core vesicles in bovine chromaffin cells.
    EMBO J. 2000 Jul 17;19(14):3586-96 PMID: 10899113
  9. Specific binding of phosphatidylinositol 4,5-bisphosphate to calcium-dependent activator protein for secretion (CAPS), a potential phosphoinositide effector protein for regulated exocytosis.
    J Biol Chem. 1998 Apr 3;273(14):8337-43 PMID: 9525942
  10. UNC-13 is required for synaptic vesicle fusion in C. elegans.
    Nat Neurosci. 1999 Nov;2(11):959-64 PMID: 10526333
  11. The activation of exocytotic sites by the formation of phosphatidylinositol 4,5-bisphosphate microdomains at syntaxin clusters.
    J Biol Chem. 2005 Apr 29;280(17):17346-52 PMID: 15741173
  12. Differential distributions of the Ca2+ -dependent activator protein for secretion family proteins (CAPS2 and CAPS1) in the mouse brain.
    J Comp Neurol. 2006 Apr 20;495(6):735-53 PMID: 16506193
  13. Membrane recognition by phospholipid-binding domains.
    Nat Rev Mol Cell Biol. 2008 Feb;9(2):99-111 PMID: 18216767
  14. Presynaptic UNC-31 (CAPS) is required to activate the G alpha(s) pathway of the Caenorhabditis elegans synaptic signaling network.
    Genetics. 2006 Feb;172(2):943-61 PMID: 16272411
  15. CAPS facilitates filling of the rapidly releasable pool of large dense-core vesicles.
    J Neurosci. 2008 May 21;28(21):5594-601 PMID: 18495893
  16. Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells.
    Mol Biol Cell. 2005 Feb;16(2):731-41 PMID: 15548590
  17. Vesicle docking in regulated exocytosis.
    Traffic. 2008 Sep;9(9):1414-24 PMID: 18445120
  18. A new method for cell permeabilization reveals a cytosolic protein requirement for Ca2+ -activated secretion in GH3 pituitary cells.
    J Biol Chem. 1989 Jun 15;264(17):10299-308 PMID: 2722869
  19. Plasmalemmal phosphatidylinositol-4,5-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells.
    J Neurosci. 2005 Mar 9;25(10):2557-65 PMID: 15758165
  20. Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform.
    Biochem J. 2000 Jul 1;349(Pt 1):247-53 PMID: 10861235
  21. Regulation of insulin exocytosis by Munc13-1.
    J Biol Chem. 2003 Jul 25;278(30):27556-63 PMID: 12871971
  22. Tissue distribution of Ca2+-dependent activator protein for secretion family members CAPS1 and CAPS2 in mice.
    J Histochem Cytochem. 2007 Mar;55(3):301-11 PMID: 17164411
  23. Synaptic vesicle fusion.
    Nat Struct Mol Biol. 2008 Jul;15(7):665-74 PMID: 18618940
  24. Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin.
    J Biol Chem. 1997 Jan 24;272(4):2520-6 PMID: 8999968
  25. Small GTP-binding proteins.
    Physiol Rev. 2001 Jan;81(1):153-208 PMID: 11152757
  26. A conformational switch in syntaxin during exocytosis: role of munc18.
    EMBO J. 1999 Aug 16;18(16):4372-82 PMID: 10449403
  27. 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
  28. PKA activation bypasses the requirement for UNC-31 in the docking of dense core vesicles from C. elegans neurons.
    Neuron. 2007 Nov 21;56(4):657-69 PMID: 18031683
  29. Molecular mechanism of docking of dense-core vesicles to the plasma membrane in neuroendocrine cells.
    Med Mol Morphol. 2008 Jun;41(2):68-75 PMID: 18592160
  30. CAPS1 regulates catecholamine loading of large dense-core vesicles.
    Neuron. 2005 Apr 7;46(1):75-88 PMID: 15820695
  31. Emerging roles of presynaptic proteins in Ca++-triggered exocytosis.
    Science. 2002 Oct 25;298(5594):781-5 PMID: 12399579
  32. Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients.
    J Clin Invest. 2007 Apr;117(4):931-43 PMID: 17380209
  33. 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
  34. Alternative splicing variations in mouse CAPS2: differential expression and functional properties of splicing variants.
    BMC Neurosci. 2007 Apr 12;8:25 PMID: 17428348
  35. Binding to Rab3A-interacting molecule RIM regulates the presynaptic recruitment of Munc13-1 and ubMunc13-2.
    J Biol Chem. 2006 Jul 14;281(28):19720-31 PMID: 16704978
  36. CAPS-1 and CAPS-2 are essential synaptic vesicle priming proteins.
    Cell. 2007 Nov 16;131(4):796-808 PMID: 18022372
  37. Resolution of regulated secretion into sequential MgATP-dependent and calcium-dependent stages mediated by distinct cytosolic proteins.
    J Cell Biol. 1992 Oct;119(1):139-51 PMID: 1527165
  38. Dissecting docking and tethering of secretory vesicles at the target membrane.
    EMBO J. 2006 Aug 23;25(16):3725-37 PMID: 16902411
  39. A key role for a 145-kDa cytosolic protein in the stimulation of Ca(2+)-dependent secretion by protein kinase C.
    J Biol Chem. 1992 Nov 25;267(33):23972-81 PMID: 1429734
  40. A novel 145 kd brain cytosolic protein reconstitutes Ca(2+)-regulated secretion in permeable neuroendocrine cells.
    Cell. 1992 Sep 4;70(5):765-75 PMID: 1516133
  41. Ca(2+)-dependent activator protein for secretion is critical for the fusion of dense-core vesicles with the membrane in calf adrenal chromaffin cells.
    J Neurosci. 1999 Sep 1;19(17):7375-83 PMID: 10460244
  42. The genetics of Caenorhabditis elegans.
    Genetics. 1974 May;77(1):71-94 PMID: 4366476
  43. Neurotrophin-3 is required for proper cerebellar development.
    Nat Neurosci. 1999 Feb;2(2):115-7 PMID: 10195193
  44. C2-domains, structure and function of a universal Ca2+-binding domain.
    J Biol Chem. 1998 Jun 26;273(26):15879-82 PMID: 9632630
  45. UNC-13 and neurotransmitter release.
    Nat Neurosci. 1999 Nov;2(11):929-30 PMID: 10526324
  46. Novel Ca2+-binding protein (CAPS) related to UNC-31 required for Ca2+-activated exocytosis.
    J Biol Chem. 1997 Aug 8;272(32):19637-40 PMID: 9289490
  47. A family of Ca2+-dependent activator proteins for secretion: comparative analysis of structure, expression, localization, and function.
    J Biol Chem. 2003 Dec 26;278(52):52802-9 PMID: 14530279
  48. CAPS and syntaxin dock dense core vesicles to the plasma membrane in neurons.
    J Cell Biol. 2008 Feb 11;180(3):483-91 PMID: 18250196
  49. The Caenorhabditis elegans unc-31 gene affects multiple nervous system-controlled functions.
    Genetics. 1993 Jun;134(2):455-64 PMID: 8325482
  50. UNC-13 interaction with syntaxin is required for synaptic transmission.
    Curr Biol. 2005 Dec 20;15(24):2236-42 PMID: 16271476
  51. Munc18-1 in secretion: lonely Munc joins SNARE team and takes control.
    Trends Neurosci. 2007 Nov;30(11):564-72 PMID: 17956762
  52. Ca2+-dependent activator proteins of secretion promote vesicular monoamine uptake.
    J Biol Chem. 2009 Jan 9;284(2):1050-6 PMID: 19008227
  53. Ca2+-dependent activator protein for secretion 1 is critical for constitutive and regulated exocytosis but not for loading of transmitters into dense core vesicles.
    J Biol Chem. 2007 Jul 20;282(29):21392-403 PMID: 17540763
  54. Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs.
    Cell. 2002 Jan 11;108(1):121-33 PMID: 11792326
  55. An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming.
    Nature. 2001 Jul 19;412(6844):338-41 PMID: 11460165
  56. CAPS (mammalian UNC-31) protein localizes to membranes involved in dense-core vesicle exocytosis.
    Neuron. 1998 Jul;21(1):137-45 PMID: 9697858
  57. Membrane association domains in Ca2+-dependent activator protein for secretion mediate plasma membrane and dense-core vesicle binding required for Ca2+-dependent exocytosis.
    J Biol Chem. 2002 Jun 14;277(24):22025-34 PMID: 11927595
  58. Drosophila UNC-13 is essential for synaptic transmission.
    Nat Neurosci. 1999 Nov;2(11):965-71 PMID: 10526334
  59. UNC-31 (CAPS) is required for dense-core vesicle but not synaptic vesicle exocytosis in Caenorhabditis elegans.
    J Neurosci. 2007 Jun 6;27(23):6150-62 PMID: 17553987
  60. Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development.
    Cell. 1994 Mar 25;76(6):989-99 PMID: 8137432
  61. Formation, stabilisation and fusion of the readily releasable pool of secretory vesicles.
    Pflugers Arch. 2004 Jul;448(4):347-62 PMID: 14997396
  62. The secretory granule-associated protein CAPS2 regulates neurotrophin release and cell survival.
    J Neurosci. 2004 Jan 7;24(1):43-52 PMID: 14715936
  63. Primed vesicles can be distinguished from docked vesicles by analyzing their mobility.
    J Neurosci. 2007 Feb 7;27(6):1386-95 PMID: 17287513
  64. Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets.
    J Biol Chem. 2004 Mar 12;279(11):10730-7 PMID: 14699162
  65. CAPS acts at a prefusion step in dense-core vesicle exocytosis as a PIP2 binding protein.
    Neuron. 2004 Aug 19;43(4):551-62 PMID: 15312653
  66. Abnormal cerebellar development and foliation in BDNF-/- mice reveals a role for neurotrophins in CNS patterning.
    Neuron. 1997 Aug;19(2):269-81 PMID: 9292718
  67. Differential regulation of exocytosis by calcium and CAPS in semi-intact synaptosomes.
    Neuron. 1998 Jul;21(1):147-54 PMID: 9697859
  68. A minimal domain responsible for Munc13 activity.
    Nat Struct Mol Biol. 2005 Nov;12(11):1017-8 PMID: 16228007
  69. Regulation of atrial natriuretic peptide secretion by a novel Ras-like protein.
    J Cell Biol. 2007 Nov 5;179(3):527-37 PMID: 17984325
Article Info
Journal
Molecular neurobiology
Abbr.
Mol Neurobiol
ISSN
0893-7648
DOI
10.1007/s12035-009-8052-5
Published
2009-02-00
Epub
2009-00-23
Pages
62-72
Language
English
Region
United States
NLM ID
8900963
Subset
IM
External Links
PubMed source DOI: 10.1007/s12035-009-8052-5 View journal details
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