Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression

Abstract

Lipid microdomains ("rafts") are dynamic, nanoscale regions of the plasma membrane enriched in cholesterol and glycosphingolipids, that possess distinctive physicochemical properties including higher order than the surrounding membrane. Lipid microdomain integrity is thought to affect neurotransmitter signaling by regulating membrane-bound protein signaling. Among the proteins potentially affected are monoaminergic receptors and transporters. As dysfunction of monoaminergic neurotransmission is implicated in major depressive disorder and other neuropsychiatric conditions, interactions with lipid microdomains may be of clinical importance. This systematic review evaluates what is known about the molecular relationships of monoamine transporter and receptor regulation to lipid microdomains. The PubMed/MeSH database was searched for original studies published in English through August 2017 concerning relationships between lipid microdomains and serotonin, dopamine and norepinephrine transporters and receptors. Fifty-seven publications were identified and assessed. Strong evidence implicates lipid microdomains in the regulation of serotonin and norepinephrine transporters; serotonin 1A, 2A, 3A, and 7A receptors; and dopamine D1 and β2 adrenergic receptors. Results were conflicting or more complex regarding lipid microdomain associations with the dopamine transporter, D2, D3, and D5 receptors; and negative with respect to β1 adrenergic receptors. Indirect evidence suggests that antidepressants, lipid-lowering drugs, and polyunsaturated fatty acids may exert effects on depression and suicide by altering the lipid milieu, thereby affecting monoaminergic transporter and receptor signaling. The lipid composition of membrane subdomains is involved in localization and trafficking of specific monoaminergic receptors and transporters. Elucidating precise mechanisms whereby lipid microdomains modulate monoamine neurotransmission in clinical contexts can have critical implications for pharmacotherapeutic targeting.

Quantum dots reveal heterogeneous membrane diffusivity and dynamic surface density polarization of dopamine transporter

“…The existence of distinct diffusive pools of membrane DATs is expected according to the predominant hypothesis of DAT plasma membrane organization reported in the literature. It proposes a lipid microdomain model, suggesting that DAT segregates into cholesterol- and glycosphingolipid-rich nanodomains that provide the necessary microenvironment for efficient dopamine reuptake and potentially serve as “hot spots” for the recruitment of DAT binding partners or constitutive/regulated endocytosis [11–13,49,55]. When we examined factors involved in the regulation of DAT diffusion dynamics and cell surface distribution, we found that the lateral motion of DAT was primarily regulated through two mechanisms: (i) confinement and retention of a large fraction of DATs at the cell edge and (ii) limited diffusive DAT penetration into the flat membrane regions despite the existence of a highly mobile fraction in thin membrane protrusions.…”

Monoamine transporters: structure, intrinsic dynamics and allosteric regulation

“…The tightly regulated structural dynamics of MATs do not solely enable the translocation of substrates and ions. They mediate the assembly, complexation or oligomerization of MATs, their sub-cellular localization, and selective activation of downstream signals 8,16,46,85,96 . Post-translational modifications of MATs have major roles in maintaining subcellular localization and interactions with regulatory proteins 8–11,46,85 .…”

“…The tightly regulated structural dynamics of MATs do not solely enable the translocation of substrates and ions. They mediate the assembly, complexation or oligomerization of MATs, their sub-cellular localization, and selective activation of downstream signals 8,16,46,85,96 .…”

Acute Statin Treatment Improves Antibody Accumulation in EGFR- and PSMA-Expressing Tumors

“…Cholesterol depletion is performed in laboratory protocols to pharmacologically modulate caveolae-mediated endocytosis (reviewed in ref. 22) by using CAV1 small interfering RNA (siRNA), CAV1-knockout mice, inhibition of cholesterol synthesis (statins), removal of cholesterol (methyl-b-cyclodextrin), and sequestration of cholesterol (filipin and nystatin). Cholesterol depletion perturbs not only caveolae but also clathrin-dependent endocytosis (23,24), fast endophilin-mediated endocytosis (FEME) and the CLIC/GEEC pathway (25,26).…”