Direct affinity of dopamine to lipid membranes investigated by Nuclear Magnetic Resonance spectroscopy

Abstract

Dopamine, a naturally occurring neurotransmitter, plays an important role in the brain's reward system and acts on sensory receptors in the brain. Neurotransmitters are contained in lipid membraned vesicles and are released by exocytosis. All neurotransmitters interact with transport and receptor proteins in glial cells, on neuronal dendrites, and at the axonal button, and also must interact with membrane lipids. However, the extent of direct interaction between lipid membranes in the absence of receptors and transport proteins has not been extensively investigated. In this report, we use UV and NMR spectroscopy to determine the affinity and the orientation of dopamine interacting with lipid vesicles made of either phosphatidylcholine (PC) or phosphatidylserine (PS) lipids which are primary lipid components of synaptic vesicles. We quantify the interaction of dopamine's aromatic ring with lipid membranes using our newly developed method that involves reference spectra in hydrophobic environments. Our measurements show that dopamine interacts with lipid membranes primarily through the aromatic side opposite to the hydroxyl groups, with this aromatic side penetrating deeper into the hydrophobic region of the membrane. Since dopamine's activity involves its release into extracellular space, we have used our method to also investigate dopamine's release from lipid vesicles. We find that dopamine trapped inside PC and PS vesicles is released into the external solution despite its affinity to membranes. This result suggests that dopamine's interaction with lipid membranes is complex and involves both binding as well as permeation through lipid bilayers, a combination that could be an effective trigger for apoptosis of dopamine-generating cells.

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

“…The subsequent simulations with an alternative molecular mechanics force field methodology (OPLS vs. CHARMM) provided similar observations [42,53]. These theoretical studies indicating strong dopamine-membrane association were further validated by calorimetric [62], nuclear magnetic resonance spectroscopy [63], and fluorescence microscopy [64] experiments.…”

“…Various simulation studies [42,54,60,61] and biophysical experiments [51][52][53][54][62][63][64][65][66][67] corroborate this mechanistic division; however, there are notable exceptions to the rule when focusing on the available receptor protein structures and possible MLCs.…”

“…Endocannabinoids such as anandamide, which are derived directly from fatty acids and act as retrograde transmitters [50], deep membrane penetration, and lipid-like dynamics, are to be expected, but the level of membrane permeation or adherence is less evident for the conventional NTs. In fact, several computational and experimental studies have provided solid evidence on the effects of specific NT-lipid interactions and, moreover, highlighted the potential importance of membrane lipid composition (MLC) imbalances for neurological diseases [42,48,[51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67].…”

Changes in the blood plasma lipidome associated with response to atypical antipsychotic treatments in schizophrenia

“…Specifically, PS lipids are involved in dopamine release in the brain (Matam et al, 2016). Thus, we hypothesized that the antipsychotic-induced decrease in PS (Figure 3) could be associated with cognitive deficits in schizophrenia, resulting in worse outcomes in some components of the PANSS scale due changes in the dopamine release.…”

“…Although the results show that PS lipids might be a potential biomarker for poor response to antipsychotics, further investigations are needed to confirm this hypothesis. In addition, PS lipids also can act as a messenger in apoptosis processes (Matam et al, 2016), suggesting a possible role in dopaminergic synapses.…”