Calcium Assists Dopamine Release by Preventing Aggregation on the Inner Leaflet of Presynaptic Vesicles

Mokkila, Sini; Postila, Pekka A.; Rissanen, Sami; Juhola, Hanna; Vattulainen, Ilpo; Róg, Tomasz

doi:10.1021/acschemneuro.6b00395

Cited by 17 publications

(35 citation statements)

References 54 publications

(131 reference statements)

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“…3). This membrane preference of dopamine is predicted to be prevented almost entirely by the neutral MLC, and high calcium levels present inside the presynaptic vesicles based on the simulations and free energy calculations [58]. Nevertheless, the mechanisms for detachment of lipophilic NTs and drugs from various membranes in the synapse remain mostly unknown and, thus, require more scrutiny in the future.…”

Section: Presynaptic Vesicle: Three Fail-safes For Assuring Efficientmentioning

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%

“…Reproduced with the permission from ref. [58]. Copyright 2017 American Chemical Society regulating the MLC tightly, the NT entry would follow either the membrane-independent or membrane-dependent mechanism [42] (Fig.…”

Section: Synaptic Receptor Types Vs Lipid-neurotransmitter Associationmentioning

confidence: 99%

“…There are at least three fail-safe mechanisms for preventing the unwanted membrane aggregation onto the inner leaflet of the vesicle (Fig. 5) [58]. Firstly, the lumen of the vesicle is kept relatively acidic (pH 5.6) in comparison with the physiological pH (7.4).…”

Section: Presynaptic Vesicle: Three Fail-safes For Assuring Efficientmentioning

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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Section: Presynaptic Vesicle: Three Fail-safes For Assuring Efficientmentioning

confidence: 98%

Section: Evidence Of Direct Neurotransmitter-lipid Interactionsmentioning

confidence: 99%

Section: Synaptic Receptor Types Vs Lipid-neurotransmitter Associationmentioning

confidence: 99%

Section: Presynaptic Vesicle: Three Fail-safes For Assuring Efficientmentioning

confidence: 99%

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A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

Postila

Róg

2019

Mol Neurobiol

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“…The serotonin derived hormone melatonin associates with planar bilayers in a similar orientation, however this has only been measured qualitatively but not quantitatively (16,17). Another study indicated that the electrostatic interaction of dopamine with the inner leaflet of presynaptic vesicles must be screened to prevent NT aggregation and thus facilitate synaptic release (18).…”

Section: Introductionmentioning

confidence: 99%

Association of Model Neurotransmitters with Lipid Bilayer Membranes

Loesche

Heinrich

Josey

et al. 2019

Preprint

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Aimed to reproduce the results of electrophysiological studies of synaptic signal transduction, conventional models of neurotransmission are based on the specific binding of neurotransmitters to ligand-gated receptor ion channels. However, the complex kinetic behavior observed in synaptic transmission cannot be reproduced in a standard kinetic model without the ad hoc postulation of additional conformational channel states. On the other hand, if one invokes unspecific neurotransmitter adsorption to the bilayer-a process not considered in the established models-the electrophysiological data can be rationalized with only the standard set of three conformational receptor states that also depend on this indirect coupling of neurotransmitters via their membrane interaction. Experimental verification has been difficult because binding affinities of neurotransmitters to the lipid bilayer are low. We quantify this interaction with surface plasmon resonance to measure equilibrium dissociation constants in neurotransmitter membrane association. Neutron reflectometry on artificial membranes reveals the structural aspects of neurotransmitters association with zwitterionic and anionic bilayers. We establish that serotonin interacts nonspecifically with the membrane at physiologically relevant concentrations whilst GABA (γaminobutyric acid) does not. Surface plasmon resonance shows that serotonin adsorbs with millimolar affinity and neutron reflectometry shows that it penetrates the membrane deeply whereas GABA is excluded from the bilayer. SignificanceReceptor ion channels in the postsynaptic membrane and their neurotransmitter agonists enable fast communication between neuronal cells. Electrophysiology studies reveal surprisingly complex kinetics that apparently require a variety of protein conformational states for their quantitative interpretation, but an alternate hypothesis invoking neurotransmitter membrane association reduces the complexity of the underlying reaction schemes significantly. While their affinity may be low, and is hard to quantify experimentally, neurotransmitter membrane association can be relevant because of their large temporary concentration in the synaptic cleft. With thermodynamic and structural measurements we quantify membrane-bound states of serotonin, establishing this neurotransmitter as membrane-affine, whereas the affinity of the more hydrophilic GABA is too low to register in our sensitivity-optimized measurement techniques.

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Electricity‐Wettability Controlled Fast Transmission of Dopamine in Nanochannels

Fang

Yang

et al. 2023

Small

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Achieving fast transmembrane transmission of molecules in organisms is a challenging problem. Inspired by the transport of Dopmine (DA) in organisms, the DA transporter (DAT) binds to DA in a way that has a ring recognition (the recognition group is the tryptophan group). Herein, D‐Tryptophan‐pillar[5]arene (D‐Trp‐P5) functionalized conical nanochannel is constructed to achieve fast transmission of DA. The D‐Trp‐P5 functionalized nanochannel enables specific wettability recognition of DA molecules and has great cycle stability. With the controlling of voltage to wettability, the transport flux of DA is up to 499.73 nmol cm−2 h−1 at −6 V, 16.88 times higher than that under positive voltages. In response to these results, a high‐throughput DA transport device based on controlled electricity‐wettability is provided.

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Calcium Assists Dopamine Release by Preventing Aggregation on the Inner Leaflet of Presynaptic Vesicles

Cited by 17 publications

References 54 publications

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

Association of Model Neurotransmitters with Lipid Bilayer Membranes

Electricity‐Wettability Controlled Fast Transmission of Dopamine in Nanochannels

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