DSCR1/RCAN1 regulates vesicle exocytosis and fusion pore kinetics: implications for Down syndrome and Alzheimer's disease

Human Molecular Genetics
Damien J KeatingMelanie A Pritchard

Abstract

Genes located on chromosome 21, over-expressed in Down syndrome (DS) and Alzheimer's disease (AD) and which regulate vesicle trafficking, are strong candidates for involvement in AD neuropathology. Regulator of calcineurin activity 1 (RCAN1) is one such gene. We have generated mutant mice in which RCAN1 is either over-expressed (RCAN1(ox)) or ablated (Rcan1-/-) and examined whether exocytosis from chromaffin cells, a classic cellular model of neuronal exocytosis, is altered using carbon fibre amperometry. We find that Rcan1 regulates the number of vesicles undergoing exocytosis and the speed at which the vesicle fusion pore opens and closes. Cells from both Rcan1-/- and RCAN1(ox) mice display reduced levels of exocytosis. Changes in single-vesicle fusion kinetics are also evident resulting in the less catecholamine released per vesicle with increasing Rcan1 expression. Acute calcineurin inhibition did not replicate the effect of RCAN1 overexpression. These changes are not due to alterations in Ca2+ entry or the readily releasable vesicle pool size. Thus, we illustrate a novel regulator of vesicle exocytosis, Rcan1, which influences both exocytotic rate and vesicle fusion kinetics. If Rcan1 functions similarly in neurons then ov...Continue Reading

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Citations

Oct 4, 2011·The Journal of Biological Chemistry·Min-Su JungSul-Hee Chung
Jan 7, 2009·The Journal of Experimental Medicine·Yong Jun YangTong-Jun Lin
Aug 5, 2008·Human Molecular Genetics·Yong YuMelanie A Pritchard
Apr 19, 2012·Human Molecular Genetics·Katherine R MartinMelanie A Pritchard
May 7, 2013·Journal of Medical Genetics·Katherine R MartinMelanie A Pritchard
Mar 3, 2011·PloS One·Mara DierssenCristina Fillat
Nov 13, 2012·PloS One·Vanessa H BraitChristopher G Sobey
Mar 31, 2012·Current Gerontology and Geriatrics Research·Guido N VacanoDavid Patterson
Jul 11, 2014·Oxidative Medicine and Cellular Longevity·Heshan PeirisDamien J Keating
Mar 3, 2017·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·A M MartinD J Keating
Jun 3, 2014·Journal of Cardiovascular Pharmacology·Lijie YanShanling Wang
Nov 18, 2015·Journal of Cellular Physiology·Ravinarayan RaghupathiDamien J Keating
Apr 12, 2013·International Journal of Molecular Sciences·Michael P HunterJohn P O'Bryan
Mar 5, 2016·Journal of Neurochemistry·Peter ThornDamien J Keating
Jan 26, 2016·PloS One·Jamie R K MarlandMichael A Cousin
Aug 14, 2009·The European Journal of Neuroscience·Thomas LadasDavid M Katz
Oct 19, 2010·Analytical and Bioanalytical Chemistry·Bryce J Marquis, Christy L Haynes
Mar 23, 2017·Endocrinology·Alyce M MartinDamien J Keating
Oct 6, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yili Wu, Weihong Song
May 11, 2013·Metallomics : Integrated Biometal Science·Clare DuncanAnthony R White
Oct 9, 2013·The Journal of Physiology·Ravinarayan RaghupathiDamien J Keating
Nov 6, 2018·EMBO Reports·David RotterBeverly A Rothermel
Nov 3, 2017·Clinical and Experimental Pharmacology & Physiology·Heshan Peiris, Damien J Keating
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Feb 15, 2017·Molecular Neurodegeneration·Katarzyna Marta ZoltowskaOksana Berezovska
Sep 24, 2020·International Journal of Molecular Sciences·Carmen Martínez-Cué, Noemí Rueda
Nov 9, 2012·Journal of Neurochemistry·Mark P ZaninDamien J Keating
Jul 24, 2018·Frontiers in Cellular Neuroscience·Jacqueline Vásquez-NavarreteAna M Cárdenas
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