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

Jan 9, 2008Human molecular genetics

How DSCR1/RCAN1 Controls Nerve Cell Release and Fusion Timing: Possible Links to Down Syndrome and Alzheimer's Disease

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Mutant mice with either over-expressed or ablated Rcan1 show reduced exocytosis from chromaffin cells.

Rcan1 regulates both the number of vesicles undergoing exocytosis and the speed of vesicle fusion pore dynamics.
Exocytosis levels are decreased in cells from both Rcan1-/- and RCAN1(ox) mice.
Increased Rcan1 expression is associated with reduced catecholamine release per vesicle.
Acute inhibition of calcineurin does not replicate the effects seen with RCAN1 overexpression.
Changes in exocytosis are not linked to alterations in calcium entry or the size of the readily releasable vesicle pool.
The involvement of Rcan1 in vesicle exocytosis may impact neurotransmission in Down syndrome and Alzheimer's disease.

AI simplified

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.

Full Text

Full text is available at the source.

View full text ↗

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

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief