Indiana University-Purdue University Indianapolis (IUPUI) / The serotonergic system in the brain is necessary for neurophysiological
processes related to mood, sleep, and cognitive regulation. This system is primarily
regulated through the transport of extracellular serotonin (5-HT) into neuron terminals by
the serotonin transporter (SERT). The activity of SERT is thought to be modulated in part
by cholesterol and lipid rich microdomains within the plasma membrane where SERT
localizes. However, experiments related to the mechanism of membrane cholesterol on
SERT function in the brain has yielded conflicting results and no studies have examined
the contribution of cholesterol biosynthetic intermediates in regulating SERT function.
To address this knowledge gap, this dissertation examined the neuropharmacological
effects of the highly prescribed cholesterol-lowering statin drugs on SERT-dependent 5-
HT uptake into neurons. Unexpectedly, statin treatment increased SERT-dependent 5-HT
uptake in a neuron cell model, and increased in vivo 5-HT content in synaptosomes. The
mechanistic findings demonstrated that (1) statins enhanced activity of SERT rather than
altered distribution at the membrane, (2) statins increased 5-HT uptake in a manner that is
independent of cholesterol per se but is mediated in part by the cholesterol biosynthetic
intermediates of the isoprenylation pathway, namely farnesyl pyrophosphate (FPP) and
geranylgeranyl pyrophosphate (GGPP), (3) direct inhibition of the isoprenylation
pathway through inhibition of GGPP enzyme geranylgeranyl transferase (GGT) also
increased 5-HT uptake in a SERT-dependent manner, and (4) increased 5-HT uptake by
statins or GGT inhibition was dependent on Ca2+/calmodulin-dependent protein kinase
(CAMKII).
Our results provide a novel role for lipid signaling in regulating SERT and a
newly identified function of the isoprenylation pathway in the brain. These results also
provide a possible explanation for the adverse neurological effects associated with the
widely prescribed statin drugs.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/26377 |
| Date | 07 1900 |
| Creators | Deveau, Carmen Marie |
| Contributors | Yamamoto, Bryan K., Sheets, Patrick L., Sullivan, William J., Atwood, Brady K., Brustovetsky, Nickolay |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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