Expression and function of the rat vesicular monoamine transporter 2

2008 ◽  
Vol 294 (4) ◽  
pp. C1004-C1011 ◽  
Author(s):  
Yoav Adam ◽  
Robert H. Edwards ◽  
Shimon Schuldiner
Keyword(s):  
Structural Data ◽  
Monoamine Transporters ◽  
Substrate Molecule ◽  
Electrogenic Transport ◽  
Multidrug Transporters ◽  
The Central Nervous System ◽  
Vesicular Monoamine Transporters ◽  
Vesicular Transporters ◽  
High Level ◽  
And Function

The vesicular monoamine transporters (VMATs) are essential proteins, involved in the storage of monoamines in the central nervous system and in endocrine cells, in a process that involves exchange of 2H+with one substrate molecule. The VMATs interact with various native substrates and clinically relevant drugs and display the pharmacological profile of multidrug transporters. Vesicular transporters suffer from a lack of biochemical and structural data due to the difficulties in their expression. In this work we present the high-level expression of rat VMAT2 (rVMAT2) in a stable a human embryonic kidney cell line (HEK293), generated using the resistance to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) conferred by the protein. In addition, we describe novel procedures for the solubilization and purification of active protein, and its reconstitution into proteoliposomes. The partially purified protein in detergent binds the inhibitor tetrabenazine and, after reconstitution, displays high levels of ΔμH+-driven electrogenic transport of serotonin. The reconstituted purified rVMAT2 has wild-type affinity for serotonin, and its turnover rate is ∼0.4 substrate molecule/s.

scholarly journals The ins and outs of vesicular monoamine transporters

2018 ◽  
Vol 150 (5) ◽  
pp. 671-682 ◽  
Author(s):  
Dana Yaffe ◽  
Lucy R. Forrest ◽  
Shimon Schuldiner
Keyword(s):  
High Resolution ◽  
Conformational Equilibrium ◽  
Structural Data ◽  
Conformational Transitions ◽  
Vesicular Monoamine Transporter ◽  
Monoamine Transporters ◽  
Detailed Understanding ◽  
Transport Cycle ◽  
Vesicular Monoamine Transporters ◽  
Homology Models

The H+-coupled vesicular monoamine transporter (VMAT) is a transporter essential for life. VMAT mediates packaging of the monoamines serotonin, dopamine, norepinephrine, and histamine from the neuronal cytoplasm into presynaptic vesicles, which is a key step in the regulated release of neurotransmitters. However, a detailed understanding of the mechanism of VMAT function has been limited by the lack of availability of high-resolution structural data. In recent years, a series of studies guided by homology models has revealed significant insights into VMAT function, identifying residues that contribute to the binding site and to specific steps in the transport cycle. Moreover, to characterize the conformational transitions that occur upon binding of the substrate and coupling ion, we have taken advantage of the unique and powerful pharmacology of VMAT as well as of mutants that affect the conformational equilibrium of the protein and shift it toward defined conformations. This has allowed us to identify an important role for the proton gradient in driving a shift from lumen-facing to cytoplasm-facing conformations.

Natural Products for the Treatment of Neurodegenerative Diseases

2020 ◽  
Vol 27 (34) ◽  
pp. 5790-5828 ◽  
Author(s):  
Ze Wang ◽  
Chunyang He ◽  
Jing-Shan Shi
Keyword(s):  
Nervous System ◽  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Neuroprotective Effect ◽  
Rapid Development ◽  
New Drugs ◽  
Progressive Degeneration ◽  
Cord Injury ◽  
The Central Nervous System ◽  
And Function

Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. Alzheimer's Disease (AD), Parkinson's Disease (PD) and Spinal Cord Injury (SCI) are the common neurodegenerative diseases, which typically occur in people over the age of 60. With the rapid development of an aged society, over 60 million people worldwide are suffering from these uncurable diseases. Therefore, the search for new drugs and therapeutic methods has become an increasingly important research topic. Natural products especially those from the Traditional Chinese Medicines (TCMs), are the most important sources of drugs, and have received extensive interest among pharmacist. In this review, in order to facilitate further chemical modification of those useful natural products by pharmacists, we will bring together recent studies in single natural compound from TCMs with neuroprotective effect.

Anatomy for Dental Students

2013 ◽  
Author(s):  
Martin E. Atkinson
Keyword(s):  
Clinical Practice ◽  
Dental Students ◽  
Multiple Choice Questions ◽  
Developmental Anatomy ◽  
Form And Function ◽  
Full Color ◽  
Online Resource ◽  
The Central Nervous System ◽  
And Function ◽  
Key Resources

Anatomy for Dental Students, Fourth Edition, demonstrates and explains all the anatomy needed for a modern dentistry undergraduate course. This text covers developmental anatomy, the thorax, the central nervous system, and the head and neck with an emphasis on the practical application of anatomical knowledge. This new edition has been extensively revised and updated in line with contemporary teaching and dental practice. Over 300 new full color diagrams map all the anatomical regions that dental students need to know, while the lively and accesible text guides the reader's learning. Throughout Clinical Application Boxes demonstrate how the form and function of anatomy have consequences for clinical practice. Sidelines boxes contain additional descriptions for key anatomical structures. This text is supported by an Online Resource Centre with multiple choice questions, drag and drop figure exercises, and links to key resources to help readers to consolidate and extend their knowledge of anatomy. Anatomy for Dental Students brings together anatomical structure, function, and their relationship to clinical practice, making it ideal for dental students.

scholarly journals Data Reduction in the String Space for Efficient kNN Classification Through Space Partitioning

2020 ◽  
Vol 10 (10) ◽  
pp. 3356 ◽  
Author(s):  
Jose J. Valero-Mas ◽  
Francisco J. Castellanos
Keyword(s):  
Data Reduction ◽  
Structural Data ◽  
Data Representation ◽  
Space Partitioning ◽  
Classification Rate ◽  
Symbolic Data ◽  
Knn Classifier ◽  
Initial Dataset ◽  
Low Efficiency ◽  
High Level

Within the Pattern Recognition field, two representations are generally considered for encoding the data: statistical codifications, which describe elements as feature vectors, and structural representations, which encode elements as high-level symbolic data structures such as strings, trees or graphs. While the vast majority of classifiers are capable of addressing statistical spaces, only some particular methods are suitable for structural representations. The kNN classifier constitutes one of the scarce examples of algorithms capable of tackling both statistical and structural spaces. This method is based on the computation of the dissimilarity between all the samples of the set, which is the main reason for its high versatility, but in turn, for its low efficiency as well. Prototype Generation is one of the possibilities for palliating this issue. These mechanisms generate a reduced version of the initial dataset by performing data transformation and aggregation processes on the initial collection. Nevertheless, these generation processes are quite dependent on the data representation considered, being not generally well defined for structural data. In this work we present the adaptation of the generation-based reduction algorithm Reduction through Homogeneous Clusters to the case of string data. This algorithm performs the reduction by partitioning the space into class-homogeneous clusters for then generating a representative prototype as the median value of each group. Thus, the main issue to tackle is the retrieval of the median element of a set of strings. Our comprehensive experimentation comparatively assesses the performance of this algorithm in both the statistical and the string-based spaces. Results prove the relevance of our approach by showing a competitive compromise between classification rate and data reduction.

L2 acquisition of the bei passive in Mandarin Chinese: A constructionist approach

2020 ◽  
Vol 9 (2) ◽  
pp. 169-198
Author(s):  
Chen Chen ◽  
Feng-hsi Liu
Keyword(s):  
Mandarin Chinese ◽  
Choice Task ◽  
L2 Acquisition ◽  
Low Level ◽  
Passive Construction ◽  
Form And Function ◽  
L2 Learners ◽  
Constructionist Approach ◽  
High Level ◽  
And Function

Abstract A major claim in the constructionist approach to language acquisition is that grammar is learned by pairings of form and function. In this study we test this claim by examining how L2 learners of Mandarin Chinese acquire the bei passive construction, a construction that is associated with the meaning of adversity. Our goal is to find out whether L2 learners make the association between the passive and adversity. Participants performed a sentence choice task under four conditions: an adversative context with an adversative verb, an adversative context with a neutral verb, a neutral context with a neutral verb and a positive context with a neutral verb. In each context participants were asked to select either the bei passive construction or its active counterpart. We found that high-level learners consistently chose the bei passive significantly more in adversative contexts than in non-adversative contexts regardless of the connotations of the verbs, while low-level learners made the distinction half of the time. In addition, while low-level learners did not yet associate adversity with the form of the construction, high-level learners did. We conclude that L2 learners do learn the bei passive construction as a form-meaning pair. The constructionist approach is supported.

scholarly journals Alpha2-Adrenoblockers Regulate Development of Oxidative Stress and Cognitive Behaviour of Rats under Chronic Acoustic Stress Conditions

2021 ◽  
Vol 14 (6) ◽  
pp. 529
Author(s):  
Magdalina Melkonyan ◽  
Ashkhen Manukyan ◽  
Lilit Hunanyan ◽  
Artem Grigoryan ◽  
Hayk Harutyunyan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Noise Exposure ◽  
Male Rats ◽  
Behavioral Activity ◽  
Induced Stress ◽  
Y Maze ◽  
Cognitive Behaviour ◽  
The Central Nervous System ◽  
High Level ◽  
Environment Noise

Noise is a wide-spread stress factor in modern life produced by urbanization, traffic, and an industrialized environment. Noise stress causes dysfunction and neurotransmission impairment in the central nervous system, as well as changes in hormone levels. In this study, we have examined the level of α-Tocopherol (α-T) and malondialdehyde (MDA) in plasma and the erythrocytes’ membrane (EM), as well as the behavioral characteristics of a noise-induced stress model in rats. In addition, the modulating effect of α2-adrenoblockers, beditin, and mesedin on the aforementioned parameters has been investigated. For these purposes, albino male rats were divided into four groups: (1) untreated; (2) noise-exposed, (3) noise-exposed and beditin-treated (2 mg/kg, i.p.), and (4) noise-exposed and mesedin-treated (10 mg/kg, i.p.) animals. Noise-exposed groups were treated with 91dBA noise on 60 days with a daily duration of 8 h. Increased MDA and decreased α-T levels in plasma and EM were observed upon chronic high-level noise exposure. Locomotor and behavioral activity assessed with a Y-maze revealed disorientation and increased anxiety under chronic noise exposure. Prominently, α2-adrenoblockers alleviated both behavioral deficits and oxidative stress, providing evidence for the involvement of α2-adrenoceptor in the pathophysiology of noise-induced stress.

scholarly journals Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 834
Author(s):  
Anima M. Schäfer ◽  
Henriette E. Meyer zu Schwabedissen ◽  
Markus Grube
Keyword(s):  
Organic Anion ◽  
Physiological Role ◽  
Point Of View ◽  
Efflux Transporters ◽  
Organic Anion Transporting Polypeptides ◽  
Current State ◽  
P Glycoprotein ◽  
The Central Nervous System ◽  
And Function ◽  
Uptake Transporters

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

scholarly journals Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Peng Chen ◽  
Hongyang Jing ◽  
Mingtao Xiong ◽  
Qian Zhang ◽  
Dong Lin ◽  
...  
Keyword(s):  
Neural Development ◽  
Protein Level ◽  
Brain Regions ◽  
Postmortem Brain ◽  
Pathophysiological Mechanism ◽  
Brain Disorders ◽  
Spine Density ◽  
Genes Encoding ◽  
High Level ◽  
And Function

AbstractThe genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1–LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.

Sign in / Sign up

Export Citation Format

Share Document