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Computational evaluation of the energetics of substrate binding, transport and release events of neurotransmitter transporters at the molecular level is a challenge, as the structural transitions of these membrane proteins involve coupled global and local changes that span time scales of several orders of magnitude, from nanoseconds to seconds. Here, we provide a quantitative assessment of the energetics of dopamine (DA) translocation through the human DA transporter (hDAT), using a combination of molecular modeling, simulations and analysis tools. DA binding and unbinding events, which generally involve local configurational changes, are evaluated using free energy perturbation or adaptive biasing force methods. The global transitions between the outward-facing state (OFS) to the inward-facing state (IFS), on the other hand, require a dual-boost accelerated molecular dynamics (aMD) simulations. We present results on DA binding/unbinding energetics under different conditions, as well as the conformational energy landscape of hDAT in both DA-bound and -unbound states. The study provides a tractable method of approach for quantitative evaluation of substrate binding energetics and efficient estimation of conformational energy landscape, in general.
This article was published in the following journal.
Name: The journal of physical chemistry. B
Quantification of the tracer distribution would add objectivity to the visual assessments of dopamine transporter (DAT) single photon emission computed tomography (SPECT) data. Our study aimed to eval...
The human dopamine transporter (hDAT) plays a major role in dopamine homeostasis and regulation of neurotransmission by clearing dopamine from the extracellular space using secondary active transport....
One of the hallmarks of ventral midbrain dopamine (DA)-releasing neurons is membrane hyperpolarization in response to somato-dendritic D receptors (D Rs) stimulation. At early postnatal age, under sus...
Catecholamines play an important regulatory role in cutaneous wound healing. The exact role of dopamine in human epidermis has yet to be fully elucidated. Current published evidence describes its diff...
Traumatic brain injury can reduce striatal dopamine levels. The cause of this is uncertain, but is likely to be related to damage to the nigrostriatal system. We investigated the pattern of striatal d...
The purpose of the study is to investigate the functional state of dopamine cells and the dopamine transporter in ADHD subjects and controls to assess the effects of chronic methylphenidat...
Healthy subjects will be enrolled in this study. Each subject will be scanned twice with F18-FP-CIT PET which is commercially available. F18-FP-CIT reflects dopamine transporter availabili...
This study will examine changes in brain dopamine transporter activity before and after antidepressant therapy.
We examine the usage of Dopamine blockers in OCD patients. We want to examine their frequency of usage, compare the course of the disease between those who receive and those who do not rec...
Donor pre-treatment with dopamine reduces injury to the kidney graft with consequences on the clinical performance immediately after transplantation: Donor dopamine reduces the requirement...
Drugs that bind to but do not activate DOPAMINE RECEPTORS, thereby blocking the actions of dopamine or exogenous agonists. Many drugs used in the treatment of psychotic disorders (ANTIPSYCHOTIC AGENTS) are dopamine antagonists, although their therapeutic effects may be due to long-term adjustments of the brain rather than to the acute effects of blocking dopamine receptors. Dopamine antagonists have been used for several other clinical purposes including as ANTIEMETICS, in the treatment of Tourette syndrome, and for hiccup. Dopamine receptor blockade is associated with NEUROLEPTIC MALIGNANT SYNDROME.
The naturally occurring form of DIHYDROXYPHENYLALANINE and the immediate precursor of DOPAMINE. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to DOPAMINE. It is used for the treatment of PARKINSONIAN DISORDERS and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system.
Any drugs that are used for their effects on dopamine receptors, on the life cycle of dopamine, or on the survival of dopaminergic neurons.
A subtype of dopamine D1 receptors that has higher affinity for DOPAMINE and differentially couples to GTP-BINDING PROTEINS.
One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of receptors (RECEPTORS, DOPAMINE) mediate its action.
Ophthalmology is the branch of medicine that is devoted to the study and treatment of eye diseases. As well as mild visual defects correctable by lenses, ophthalmology is concerned with glaucoma, uveitis and other serious conditions affecting the eye, ...