Abstract：
:Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog LeuT. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed mutagenesis and by trapping the radiolabeled cocaine analog [3H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive inhibition of dopamine transport by cocaine.
journal_name
Nat Neuroscijournal_title
Nature neuroscienceauthors
Beuming T,Kniazeff J,Bergmann ML,Shi L,Gracia L,Raniszewska K,Newman AH,Javitch JA,Weinstein H,Gether U,Loland CJdoi
10.1038/nn.2146subject
Has Abstractpub_date
2008-07-01 00:00:00pages
780-9issue
7eissn
1097-6256issn
1546-1726pii
nn.2146journal_volume
11pub_type
杂志文章abstract：:To determine the number of open Ca(2+) channels necessary for transmitter release at the inhibitory basket cell-granule cell synapse in rat hippocampus, we combined presynaptic Ca(2+) imaging, recording of postsynaptic currents and modeling. We found that that the opening of three or fewer Ca(2+) channels triggered tr...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2461
更新日期：2010-01-01 00:00:00
abstract：:The brain transforms physical sensory stimuli into meaningful perceptions. In animals making choices about sensory stimuli, neuronal activity in successive cortical stages reflects a progression from sensation to decision. Feedforward and feedback pathways connecting cortical areas are critical for this transformation...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.4356
更新日期：2016-09-01 00:00:00
abstract：:We show that a natural behavior, exploration of a novel environment, causes DNA double-strand breaks (DSBs) in neurons of young adult wild-type mice. DSBs occurred in multiple brain regions, were most abundant in the dentate gyrus, which is involved in learning and memory, and were repaired within 24 h. Increasing neu...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3356
更新日期：2013-05-01 00:00:00
abstract：:Lateral and medial parts of entorhinal cortex (EC) convey nonspatial 'what' and spatial 'where' information, respectively, into hippocampal CA1, via both the indirect EC layer 2→ hippocampal dentate gyrus→CA3→CA1 and the direct EC layer 3→CA1 paths. However, it remains elusive how the direct path transfers distinct in...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.4517
更新日期：2017-04-01 00:00:00
abstract：:Timing is crucial to many aspects of human performance. To better understand its neural underpinnings, we used event-related fMRI to examine the time course of activation associated with different components of a time perception task. We distinguished systems associated with encoding time intervals from those related ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/85191
更新日期：2001-03-01 00:00:00
abstract：:The olfactory system faces a hard problem: on the basis of noisy information from olfactory receptor neurons (the neurons that transduce chemicals to neural activity), it must figure out which odors are present in the world. Odors almost never occur in isolation, and different odors excite overlapping populations of o...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.4444
更新日期：2017-01-01 00:00:00
abstract：:Myelinating cells, oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system produce an enormous amount of plasma membrane during the myelination process, making them particularly susceptible to disruptions of the secretory pathway. Endoplasmic reticulum stress, initiated by the accumulation of un...
journal_title：Nature neuroscience
pub_type： 杂志文章,评审
doi：10.1038/nn.2273
更新日期：2009-04-01 00:00:00
abstract：:Humans have ~400 intact odorant receptors, but each individual has a unique set of genetic variations that lead to variation in olfactory perception. We used a heterologous assay to determine how often genetic polymorphisms in odorant receptors alter receptor function. We identified agonists for 18 odorant receptors a...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3598
更新日期：2014-01-01 00:00:00
abstract：:At glutamatergic synapses, calcium influx through NMDA receptors (NMDARs) is required for long-term potentiation (LTP); this is a proposed cellular mechanism underlying memory and learning. Here we show that in lateral amygdala pyramidal neurons, SK channels are also activated by calcium influx through synaptically ac...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1450
更新日期：2005-05-01 00:00:00
abstract：:Uncovering structural regularities and architectural topologies of cortical circuitry is vital for understanding neural computations. Recently, an experimentally constrained algorithm generated a dense network reconstruction of a ∼0.3-mm3 volume from juvenile rat somatosensory neocortex, comprising ∼31,000 cells and ∼...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.4576
更新日期：2017-07-01 00:00:00
abstract：:The CNS is protected by the immune system, including cells that reside directly within the CNS and help to ensure proper neural function, as well as cells that traffic into the CNS with disease. The CNS-resident immune system is comprised mainly of innate immune cells and operates under homeostatic conditions. These m...
journal_title：Nature neuroscience
pub_type： 杂志文章,评审
doi：10.1038/nn.4475
更新日期：2017-02-01 00:00:00
abstract：:Temporal regulation of embryonic neurogenesis is controlled by hypostable transcription factors. The mechanism of the process is unclear. Here we show that the RNase III Drosha and DGCR8 (also known as Pasha), key components of the microRNA (miRNA) microprocessor, have important functions in mouse neurogenesis. Loss o...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3139
更新日期：2012-06-17 00:00:00
abstract：:Neural activity exhibits complex dynamics related to various brain functions, internal states and behaviors. Understanding how neural dynamics explain specific measured behaviors requires dissociating behaviorally relevant and irrelevant dynamics, which is not achieved with current neural dynamic models as they are le...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/s41593-020-00733-0
更新日期：2021-01-01 00:00:00
abstract：:Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3094
更新日期：2012-06-01 00:00:00
abstract：:Dendritic spikes signal synaptic integration at remote apical dendritic sites in neocortical pyramidal neurons in vitro. Do dendritic spikes have a salient signaling role under in vivo conditions, where neocortical pyramidal neurons are bombarded with synaptic input? In the present study, levels of synaptic conductanc...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1305
更新日期：2004-09-01 00:00:00
abstract：:We elucidated the intrinsic circuitry of the medial prefrontal cortex and its role in regulating fear extinction, using neuronal tracing and optogenetic stimulation in vitro and in vivo. We show that pyramidal neurons in layer 5/6 of the prelimbic medial prefrontal cortex project to pyramidal cells in layer 5/6 of the...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/s41593-018-0137-x
更新日期：2018-05-01 00:00:00
abstract：:Epilepsy is a common and refractory neurological disorder, but the neuronal regulatory mechanisms of epileptogenesis remain largely unclear. Activity-dependent transcription of genes for neurotrophins such as brain-derived neurotrophic factor (BDNF) has been shown to promote epileptogenesis; however, little is known a...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3005
更新日期：2011-12-11 00:00:00
abstract：:Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding huntingtin protein (Htt), but the mechanisms by which this mutant protein causes neurodegeneration remain unknown. Here we show that lymphoblast mitochondria from patients with HD have a lower membrane potential and ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn884
更新日期：2002-08-01 00:00:00
abstract：:Cell type-specific expression of optogenetic molecules allows temporally precise manipulation of targeted neuronal activity. Here we present a toolbox of four knock-in mouse lines engineered for strong, Cre-dependent expression of channelrhodopsins ChR2-tdTomato and ChR2-EYFP, halorhodopsin eNpHR3.0 and archaerhodopsi...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3078
更新日期：2012-03-25 00:00:00
abstract：:Although inherently linked, body form and body action may be represented in separate neural substrates. Using repetitive transcranial magnetic stimulation in healthy individuals, we show that interference with the extrastriate body area impairs the discrimination of bodily forms, and interference with the ventral prem...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1815
更新日期：2007-01-01 00:00:00
abstract：:Enduring deficits in temporal processing can be induced in the auditory cortex by rearing infant rats in the presence of low frequency-modulated noises. We found that it was possible to restore normal temporal processing, overcoming deficits induced during the critical period, by intensively training developmentally i...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2239
更新日期：2009-01-01 00:00:00
abstract：:Neural activity in visual area V4 is enhanced when attention is directed into neuronal receptive fields. However, the source of this enhancement is unclear, as most physiological studies have manipulated attention by changing the absolute reward associated with a particular location as well as its value relative to ot...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.4141
更新日期：2015-11-01 00:00:00
abstract：:An ion channel's function depends largely on its location and density on neurons. Here we used high-resolution immunolocalization to determine the subcellular distribution of the hyperpolarization-activated and cyclic-nucleotide-gated channel subunit 1 (HCN1) in rat brain. Light microscopy revealed graded HCN1 immunor...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn962
更新日期：2002-11-01 00:00:00
abstract：:In the postnatal subventricular zone (SVZ), local cues or signaling molecules released from neuroblasts limit the proliferation of glial fibrillary acidic protein (GFAP)-expressing progenitors thought to be stem cells. However, signals between SVZ cells have not been identified. We show that depolarization of neurobla...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1522
更新日期：2005-09-01 00:00:00
abstract：:Cuing covert spatial attention can increase spatial resolution. Here we pinpointed the specific locus of this effect using texture segmentation. At the level of visual cortex, texture segmentation theoretically involves passage of visual input through two layers of spatial linear filters separated by a pointwise nonli...
journal_title：Nature neuroscience
pub_type： 临床试验,杂志文章
doi：10.1038/75804
更新日期：2000-06-01 00:00:00
abstract：:In the version of this article initially published, the annotation accompanying ref. 47 ended with "though the modulation of microglia." The first word of this phrase should have been "through." The error has been corrected in the HTML and PDF versions of the article. ...
journal_title：Nature neuroscience
pub_type： 已发布勘误
doi：10.1038/s41593-018-0186-1
更新日期：2018-08-01 00:00:00
abstract：:An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title：Nature neuroscience
pub_type： 已发布勘误
doi：10.1038/s41593-019-0546-5
更新日期：2019-12-01 00:00:00
abstract：:Transmitter release is triggered by highly localized, transient increases in the presynaptic Ca(2+) concentration ([Ca(2+)]). Rapidly decaying [Ca(2+)] elevations were generated using Ca(2+) uncaging techniques, and [Ca(2+)] was measured with a low-affinity Ca(2+) indicator in a giant presynaptic terminal, the calyx o...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1417
更新日期：2005-04-01 00:00:00
abstract：:The regulation of female reproductive behaviors may involve memories of male pheromone signatures, formed in part by neural circuitry involving the olfactory bulb and hippocampus. These neural structures are the principal sites of adult neurogenesis; however, previous studies point to their independent regulation by s...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1928
更新日期：2007-08-01 00:00:00
abstract：:Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here neuromodulation of RCrusI in neurotypical humans res...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/s41593-017-0004-1
更新日期：2017-12-01 00:00:00
