Abstract
The deregulation of brain cholesterol metabolism is typical
in acute neuronal injury (such as stroke, brain trauma
and epileptic seizures) and chronic neurodegenerative
diseases (Alzheimer’s disease). Since both conditions are
characterized by excessive stimulation of glutamate receptors,
we have here investigated to which extent excitatory
neurotransmission plays a role in brain cholesterol homeostasis.
We show that a short (30 min) stimulation of
glutamatergic neurotransmission induces a small but significant
loss of membrane cholesterol, which is paralleled
by release to the extracellular milieu of the metabolite
24S-hydroxycholesterol. Consistent with a cause–effect
relationship, knockdown of the enzyme cholesterol
24-hydroxylase (CYP46A1) prevented glutamate-mediated
cholesterol loss. Functionally, the loss of cholesterol
modulates the magnitude of the depolarization-evoked
calcium response. Mechanistically, glutamate-induced
cholesterol loss requires high levels of intracellular
Ca2þ, a functional stromal interaction molecule 2 (STIM2)
and mobilization of CYP46A1 towards the plasma membrane.
This study underscores the key role of excitatory
neurotransmission in the control of membrane lipid
composition, and consequently in neuronal membrane
organization and function.
Original language | English |
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Pages (from-to) | 1764-1773 |
Number of pages | 10 |
Journal | EMBO Journal |
Volume | 31 |
Publication status | Published - 2012 |