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

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.