A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

Abstract

Synaptic neurotransmission is generally considered as a function of membrane-embedded receptors and ion channels in response to the neurotransmitter (NT) release and binding. This perspective aims to widen the protein-centric view by including another vital component-the synaptic membrane-in the discussion. A vast set of atomistic molecular dynamics simulations and biophysical experiments indicate that NTs are divided into membrane-binding and membrane-nonbinding categories. The binary choice takes place at the water-membrane interface and follows closely the positioning of the receptors' binding sites in relation to the membrane. Accordingly, when a lipophilic NT is on route to a membrane-buried binding site, it adheres on the membrane and, then, travels along its plane towards the receptor. In contrast, lipophobic NTs, which are destined to bind into receptors with extracellular binding sites, prefer the water phase. This membrane-based sorting splits the neurotransmission into membraneindependent and membrane-dependent mechanisms and should make the NT binding into the receptors more efficient than random diffusion would allow. The potential implications and notable exceptions to the mechanisms are discussed here. Importantly, maintaining specific membrane lipid compositions (MLCs) at the synapses, especially regarding anionic lipids, affect the level of NT-membrane association. These effects provide a plausible link between the MLC imbalances and neurological diseases such as depression or Parkinson's disease. Moreover, the membrane plays a vital role in other phases of the NT life cycle, including storage and release from the synaptic vesicles, transport from the synaptic cleft, as well as their synthesis and degradation.

Receptor-independent membrane mediated pathways of serotonin action

“…However, a recent discovery of the high affinity of serotonin for lipid bilayers 1 suggests that the lipid membrane may be the ubiquitously present target for such release. Indeed, it has been speculated that attachment and two-dimensional diffusion of serotonin in the lipid membrane may facilitate distal receptor binding 23 . Here, we hypothesize and demonstrate that passive serotonin-membrane interaction can give rise to an entirely receptor-independent pathway for modulating specific cell functions.…”

Serotonin Alters the Phase Equilibrium of a Ternary Mixture of Phospholipids and Cholesterol

“…In this way, the membrane represents a reservoir for these molecules. As the dimensionality of the diffusion of these compounds is reduced from three in solution to two on the membrane surface, membrane partitioning of small molecules leads to an increase in their effective concentration by a factor of ∼1,000 which is increasing the probability of binding to a cognate receptors (Sargent and Schwyzer, 1986;Brunsveld et al, 2009;Posttila and Róg, 2020).…”

“…Small molecules such as neurotransmitters often strongly interact with membranes and lipids (Peters et al, 2013;Postila et al, 2016;Josey et al, 2020;Posttila and Róg, 2020). This has several important consequences as lipids are involved in many physiological processes such as the regulation of synapse development and plasticity, presynaptic vesicle release, regulation of receptors, and cofactors of proteins in the form of nonannular lipids (Huster, 2014;Posttila and Róg, 2020). The interaction of these compounds with various lipid species may lead to alterations in lipid spontaneous curvature and dynamics, membrane hydrophobic thickness and lipid packing density, and/or membrane domain structure.…”

Dose-dependent and disease-modifying effects of striatal infusion of cholesterol in Huntington’s disease

“…Its biosynthesis occurs through a stepwise cascade involving several enzymes under transcriptional regulation by sterol regulatory element binding protein 2 (SREBP2) transcription factor (3). In the adult brain, a small amount of cholesterol continues to be synthesized locally, where it regulates multiple processes including synapse formation and maintenance, synaptic vesicle (SV) recycling, and optimal release of neurotransmitters for downstream intracellular signaling pathways (4)(5)(6)(7). Consequently, dysregulation of brain cholesterol homeostasis is linked to several chronic neurological and neurodegenerative diseases (8,9).…”