β-Adrenergic inhibition of exocytotic surface deposition of MHCII molecules in reactive astrocytes is mediated by amisyn
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Degeneration of the locus coeruleus, a noradrenergic nucleus, reduces noradrenaline bioavailability in the central nervous system and promotes neuroinflammation via reactive astrocytes, although the underlying mechanisms remain unclear. We investigated whether interferon-γ-induced expression of major histocompatibility complex class II (MHCII), a marker of pro-inflammatory reactive astrocytes, is regulated by adrenergic receptors and amisyn. β-Adrenergic, but not α-adrenergic, stimulation increased cyclic adenosine monophosphate (cAMP) and reduced MHCII expression, as detected immunocytochemically, in human and rat astrocytes. β-Adrenergic treatment altered transient exocytosis of lysosome-like vesicles, increasing event frequency and reducing fusion-pore conductance and dwell time, thereby limiting MHCII surface expression. Overexpression of wild-type amisyn inhibited surface expression of MHCII and the lysosomal marker CD63 and reduced fusion-pore conductance and dwell time. Conversely, amisyn knockdown enhanced full fusion exocytosis of larger vesicles and abolished β-adrenergic effects, indicating that amisyn mediates β-adrenergic inhibition of exocytosis and MHCII surface deposition.
Top: States in which a vesicle interacts with the plasma membrane during exocytosis: A, hemifusion; B, formation of a narrow fusion pore; C, transient fusion with reversible pore opening; D, full fusion with irreversible pore expansion. Amisyn promotes a narrow fusion pore (C) and hinders the progression to state D. Bottom: Mechanism of fusion pore regulation by β-adrenergic receptor (β-AR) and cyclic AMP; amisyn redistributes to the inner face of the plasmalemma, keeping the fusion pore constricted and reducing the probability of the fusion pore entering the full-fusion stage, thus inhibiting the density of surface-expressed MHCII antigen-presenting molecules. NA, noradrenaline.
Main points
-
Loss of noradrenergic tone after locus coeruleus degeneration promotes astrocyte-mediated neuroinflammation.
-
β-Adrenergic, but not α-adrenergic, stimulation increases cAMP and reduces MHCII expression in interferon γ-induced reactive astrocytes.
-
β-Adrenergic signalling limits MHCII surface expression by reducing fusion-pore conductance and dwell time during transient vesicle fusion.
-
Amisyn mediates this β-adrenergic inhibition; its knockdown enhances full vesicle fusion and abolishes β-adrenergic effects.
