Fingolimod--a sphingosine-like molecule inhibits vesicle mobility and secretion in astrocytes.

Abstract

In the brain, astrocytes signal to the neighboring cells by the release of chemical messengers (gliotransmitters) via regulated exocytosis. Recent studies uncovered a potential role of signaling lipids in modulation of exocytosis. Hence, we investigated whether sphingosine and the structural analog fingolimod/FTY720, a recently introduced therapeutic for multiple sclerosis, affect (i) intracellular vesicle mobility and (ii) vesicle cargo discharge from cultured rat astrocytes. Distinct types of vesicles, peptidergic, glutamatergic, and endosomes/lysosomes, were fluorescently prelabeled by cell transfection with plasmids encoding atrial natriuretic peptide tagged with mutant green fluorescent protein and vesicular glutamate transporter tagged with enhanced green fluorescent protein or by LysoTracker staining, respectively. The confocal and total internal reflection fluorescence microscopies were used to monitor vesicle mobility in the cytoplasm and near the basal plasma membrane, respectively. Sphingosine and FTY720, but not the membrane impermeable lipid analogs, dose-dependently attenuated vesicle mobility in the subcellular regions studied, and significantly inhibited stimulated exocytotic peptide and glutamate release. We conclude that in astrocytes, cell permeable sphingosine-like lipids affect regulated exocytosis by attenuating vesicle mobility, thereby preventing effective vesicle access/interaction with the plasma membrane docking/release sites.

• Authors: Saša Trkov, Matjaž Stenovec, Marko Kreft, Maja Potokar, Vladimir Parpura, Bazbek Davletov, Robert Zorec
• Journal: Glia (Glia) Vol. 60 Issue 9 Pg. 1406-16 (Sep 2012) ISSN: 1098-1136 [Electronic] United States
• PMID: 22639011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• Propylene Glycols
• Glutamic Acid
• Fingolimod Hydrochloride
• Sphingosine
• Calcium

Topics

• Animals
• Astrocytes (drug effects, metabolism)
• Calcium (metabolism)
• Dose-Response Relationship, Drug
• Exocytosis (drug effects, physiology)
• Fingolimod Hydrochloride
• Glutamic Acid (metabolism)
• Propylene Glycols (pharmacology)
• Rats
• Rats, Wistar
• Sphingosine (analogs & derivatives, pharmacology)
• Transport Vesicles (drug effects, metabolism)