TY  - JOUR
A1  - Zeitler, Stefanie
A1  - Ye, Lian
A1  - Andreyeva, Aksana
A1  - Schumacher, Fabian
A1  - Monti, Juliana
A1  - Nürnberg, Bernd
A1  - Nowak, Gabriel
A1  - Kleuser, Burkhard
A1  - Reichel, Martin
A1  - Fejtova, Anna
A1  - Kornhuber, Johannes
A1  - Rhein, Cosima
A1  - Friedland, Kristina
T1  - Acid sphingomyelinase - a regulator of canonical transient receptor potential channel 6 (TRPC6) activity
JF  - Journal of neurochemistry
N2  - Recent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM‐induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling. Canonical transient receptor potential channels 6 (TRPC6) are non‐selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John’s wort for treatment of depression disorders. Because of their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a pheochromocytoma cell line 12 neuronal cell model (PC12 rat pheochromocytoma cell line). Ca2+ imaging experiments indicated that hyperforin‐induced Ca2+ influx through TRPC6 channels is modulated by ASM activity. While antidepressants, known as functional inhibitors of ASM activity, reduced TRPC6‐mediated Ca2+ influx, extracellular application of bacterial sphingomyelinase rebalanced TRPC6 activity in a concentration‐related way. This effect was confirmed in whole‐cell patch clamp electrophysiology recordings. Lipidomic analyses revealed a decrease in very long chain ceramide/sphingomyelin molar ratio after ASM inhibition, which was connected with changes in the abundance of TRPC6 channels in flotillin‐1–positive lipid rafts as visualized by western blotting. Our data provide evidence that the ASM/ceramide system regulates TRPC6 channels likely by controlling their recruitment to specific lipid subdomains and thereby fine‐tuning their physical properties.
KW  - acid sphingomyelinase
KW  - antidepressants
KW  - ceramide
KW  - hyperforin
KW  - lipid rafts
KW  - TRPC6
Y1  - 2019
U6  - https://doi.org/10.1111/jnc.14823
SN  - 0022-3042
SN  - 1471-4159
VL  - 150
IS  - 6
SP  - 678
EP  - 690
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Gulbins, Erich
A1  - Palmada, Monica
A1  - Reichel, Martin
A1  - Lueth, Anja
A1  - Boehmer, Christoph
A1  - Amato, Davide
A1  - Mueller, Christian P.
A1  - Tischbirek, Carsten H.
A1  - Groemer, Teja W.
A1  - Tabatabai, Ghazaleh
A1  - Becker, Katrin Anne
A1  - Tripal, Philipp
A1  - Staedtler, Sven
A1  - Ackermann, Teresa F.
A1  - van Brederode, Johannes
A1  - Alzheimer, Christian
A1  - Weller, Michael
A1  - Lang, Undine E.
A1  - Kleuser, Burkhard
A1  - Grassme, Heike
A1  - Kornhuber, Johannes
T1  - Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs
JF  - Nature medicine
N2  - Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.
Y1  - 2013
U6  - https://doi.org/10.1038/nm.3214
SN  - 1078-8956
VL  - 19
IS  - 7
SP  - 934
EP  - +
PB  - Nature Publ. Group
CY  - New York
ER  -