Calcium and protons affect the interaction of neurotransmitters and anesthetics with anionic lipid membranes

Synaptic neurotransmission has recently been proposed to function via either a membrane-independent or a membrane-dependent mechanism, depending on the neurotransmitter type. In the membrane-dependent mechanism, amphipathic neurotransmitters first partition to the lipid headgroup region and then diffuse along the membrane plane to their membrane-buried receptors. However, to date, this mechanism has not been demonstrated for any neurotransmitter–receptor complex. Here, we combined isothermal calorimetry measurements with a diverse set of molecular dynamics simulation methods to investigate the partitioning of an amphipathic neurotransmitter (dopamine) and the mechanism of its entry into the ligand-binding site. Our results show that the binding of dopamine to its receptor is consistent with the membrane-dependent binding and entry mechanism. Both experimental and simulation results showed that dopamine favors binding to lipid membranes especially in the headgroup region. Moreover, our simulations revealed a ligand-entry pathway from the membrane to the binding site. This pathway passes through a lateral gate between transmembrane alpha-helices 5 and 6 on the membrane-facing side of the protein. All in all, our results demonstrate that dopamine binds to its receptor by a membrane-dependent mechanism, and this is complemented by the more traditional binding mechanism directly through the aqueous phase. The results suggest that the membrane-dependent mechanism is common in other synaptic receptors, too.

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“…Acetylcholine, however, has an affinity for lipid bilayers, especially in the presence of negatively charged lipids. 11 , 12 …”

Section: Introductionmentioning

confidence: 99%

Membrane-Dependent Binding and Entry Mechanism of Dopamine into Its Receptor

Lolicato

Juhola

Żak

et al. 2020

ACS Chem. Neurosci.

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“…14 Finally, PA was shown to increase the binding of low-molecular-weight ligands, such as neurotransmitters and anesthetics, to the lipid bilayer. 15 PA has unique biophysical properties in lipid bilayers, resulting from its molecular shape and negative charge of the headgroup. 16 PA molecules have an inverted conical shape with a relatively small headgroup in comparison with the hydrophobic part of the molecule, which promotes a negative spontaneous curvature.…”

Section: Introductionmentioning

confidence: 99%

Complex Behavior of Phosphatidylcholine–Phosphatidic Acid Bilayers and Monolayers: Effect of Acyl Chain Unsaturation

et al. 2019

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Phosphatidic acids (PAs) have many biological functions in biomembranes, e.g., they are involved in the proliferation, differentiation, and transformation of cells. Despite decades of research, the molecular understanding of how PAs effect the properties of biomembranes remains elusive. In this study, we explored the properties of lipid bilayers and monolayers composed of PAs and phosphatidylcholines (PCs) with various acyl chains. For this purpose, the Langmuir monolayer technique and atomistic molecular dynamics (MD) simulations were used to study the miscibility of PA and PC lipids and the molecular organization of mixed bilayers. The monolayer experiments demonstrated that the miscibility of membrane components strongly depends on the structure of the hydrocarbon chains, and thus, on the overall lipid shape. Interactions between PA and PC molecules vary from repulsive, for systems containing lipids with saturated and unsaturated acyl tails (strongly positive values of the excess free energy of mixing), to attractive, for systems in which all lipid tails are saturated (negative values of the excess free energy of mixing). The MD simulations provided atomistic insight into polar interactions (formation of hydrogen bonds and charge pairs) in PC-PA systems. Hbonding between PA monoanions and PCs in mixed bilayers is infrequent, and the lipid molecules interact mainly via the electrostatic interactions. However, the number of charge pairs significantly decreases with the number of unsaturated lipid chains in the PA-PC system. The PA dianions weakly interact with the zwitterionic lipids, but their headgroups are more hydrated as compared to the monoanionic form. The acyl chains in all PC-PA bilayers are more ordered comparing to single-component PC systems. In addition, depending on the combination of lipids, we observed a deeper location of the PA phosphate groups compared to the PC phosphate groups, which can alter the presentation of PAs for the peripheral membrane proteins, affecting their accessibility for binding.

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“…In particular, GABA and glutamate were shown to interact with the lipid bilayers in the presence of Ca 2+ , while acetylcholine in these conditions was repulsed [59]. Next, acetylcholine was shown to be attracted towards bilayers containing negatively charged lipids [42,56,59] and repulsed by a bilayer composed of zwitterionic lipids [56].…”

Section: Evidence Of Direct Neurotransmitter-lipid Interactionsmentioning

confidence: 98%

“…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].…”

Section: Evidence Of Direct Neurotransmitter-lipid Interactionsmentioning

confidence: 99%

“…3a, b) and experiments [51][52][53][54][55][56][62][63][64][65][66][67][68] alike show that the lipid assortment indeed affects NT dynamics profoundly. Majority of the non-peptidic NTs are attracted towards the anionic membrane models to a varying degree [42,56,59,62]. That includes even the most charged and hydrophilic NTs such as GABA or glycine as they show a moderate level of adherence on the membrane models containing anionic lipid PS (Fig.…”

Section: The Effect Of Membrane Lipid Composition On Neurotransmittermentioning

confidence: 99%

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A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

Postila

Róg

2019

Mol Neurobiol

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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.

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Calcium and protons affect the interaction of neurotransmitters and anesthetics with anionic lipid membranes

Cited by 18 publications

References 68 publications

Membrane-Dependent Binding and Entry Mechanism of Dopamine into Its Receptor

Membrane-Dependent Binding and Entry Mechanism of Dopamine into Its Receptor

Complex Behavior of Phosphatidylcholine–Phosphatidic Acid Bilayers and Monolayers: Effect of Acyl Chain Unsaturation

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

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