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

Keating, Damien J., Dubach, Daphne, Zanin, Mark P., Yu, Yong, Martin, Katherine, Zhao, Yu-Feng, Chen, Chen, Port, Sı´lvia, Arbone´s, Maria L., Mittaz, Laureane and Pritchard, Melanie A. (2008) DSCR1/RCAN1 regulates vesicle exocytosis and fusion pore kinetics: Implications for Down syndrome and Alzheimer's disease. Human Molecular Genetics, 17 7: 1020-1030. doi:10.1093/hmg/ddm374


Author Keating, Damien J.
Dubach, Daphne
Zanin, Mark P.
Yu, Yong
Martin, Katherine
Zhao, Yu-Feng
Chen, Chen
Port, Sı´lvia
Arbone´s, Maria L.
Mittaz, Laureane
Pritchard, Melanie A.
Title DSCR1/RCAN1 regulates vesicle exocytosis and fusion pore kinetics: Implications for Down syndrome and Alzheimer's disease
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
Publication date 2008-01-01
Year available 2008
Sub-type Article (original research)
DOI 10.1093/hmg/ddm374
Open Access Status Not yet assessed
Volume 17
Issue 7
Start page 1020
End page 1030
Total pages 11
Editor Wynshaw-Boris, Anthony
Davies, Kay
Hirschhorn, Joel
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject C1
110306 Endocrinology
970106 Expanding Knowledge in the Biological Sciences
110201 Cardiology (incl. Cardiovascular Diseases)
111201 Cancer Cell Biology
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 overexpression of this protein, as occurs in DS and AD brains, will reduce both the number of synaptic vesicles undergoing exocytosis and the amount of neurotransmitter released per fusion event. This has direct implications for the pathogenesis of these diseases as sufficient levels of neurotransmission are required for synaptic maintenance and the prevention of neurodegeneration and vesicle trafficking defects are the earliest hallmark of AD neuropathology.
Formatted 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 eitherover-expressed (RCAN1ox) 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 RCAN1ox 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 vesiclepool size. Thus, we illustrate a novel regulator of vesicle exocytosis, Rcan1, which influences both exocytotic mrate and vesicle fusion kinetics. If Rcan1 functions similarly in neurons then overexpression of this protein, as occurs in DS and AD brains, will reduce both the number of synaptic vesicles undergoing exocytosisand the amount of neurotransmitter released per fusion event. This has direct implications for the pathogenesis of these diseases as sufficient levels of neurotransmission are required for synaptic maintenance and the prevention of neurodegeneration and vesicle trafficking defects are the earliest hallmark of ADneuropathology.
Keyword Biochemistry & Molecular Biology
Genetics & Heredity
Biochemistry & Molecular Biology
Genetics & Heredity
BIOCHEMISTRY & MOLECULAR BIOLOGY
GENETICS & HEREDITY
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 54 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 58 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 08 Apr 2009, 23:25:56 EST by Shirley Rey on behalf of School of Biomedical Sciences