Serotonin Signaling through Lipid Membranes

Abstract

Serotonin (5-HT) is a vital modulatory neurotransmitter responsible for regulating most behaviors in the brain. An inefficient 5-HT synaptic function is often linked to various mental disorders. Primarily, membrane proteins controlling the expression and activity of 5-HT synthesis, storage, release, receptor activation, and inactivation are critical to 5-HT signaling in synaptic and extra-synaptic sites. Moreover, these signals represent information transmission across membranes. Although the lipid membrane environment is often viewed as fairly stable, emerging research suggests significant functional lipid-protein interactions with many synaptic 5-HT proteins. These protein-lipid interactions extend to almost all the primary lipid classes that form the plasma membrane. Collectively, these lipid classes and lipid-protein interactions affect 5-HT synaptic efficacy at the synapse. The highly dynamic lipid composition of synaptic membranes suggests that these lipids and their interactions with proteins may contribute to the plasticity of the 5-HT synapse. Therefore, this broader protein-lipid model of the 5-HT synapse necessitates a reconsideration of 5-HT's role in various associated mental disorders.

Keywords: cholesterol; lipids; serotonin; sphingolipids; synaptic throughput.

Figure 1

Schematic presentation of signal throughput at the serotonergic (5-HT) synapse and its dynamic regulation. 5-HT activation of metabotropic 5-HT receptors (R) is translated into cascades of intracellular signaling events or into hyperpolarization after ionotropic receptor activation. This affects gene transcription and mRNA production of genes coding for 5-HT-Rs on the one hand, but also for genes coding for lipid rheostat regulating enzymes (E) on the other hand. 5-HT-Rs are formed and integrated into the membrane, which alters future signal throughput. In parallel, lipid enzyme activity in the membrane and beyond changes the composition of the synaptic membrane. The change in the lipid environment of 5-HT-R alters their function (R*) and affects signal throughput. It is assumed that both mechanisms work permanently and interact in their effects on 5-HT synaptic throughput.