Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.107 (DAT)
 1,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ventral tegmental area (VTA) is one of the main brain regions harboring dopaminergic (DA) neurons, and plays important roles in reinforcement and motivation. Recent studies have indicated that DA neurons not only respond to rewarding stimuli, but also to noxious stimuli. Furthermore, VTA DA neurons undergo plasticity during chronic pain. Lateral and medial VTA neurons project to different brain areas, and have been characterized via their distinct electrophysiological properties. In this study, we characterized electrophysiological properties of lateral and medial VTA DA neurons using DAT-cre reporter mice, and examined their plasticity during neuropathic pain states. We observed various DA subpopulations in both the lateral and medial VTA, as defined by action potential firing patterns, independently of synaptic inputs. Our results demonstrated that lateral and medial VTA DA neurons undergo differential plasticity after peripheral nerve injury that leads to neuropathic pain. However, these changes only reside in specific DA subpopulations. This study suggests that lateral and medial VTA DA neurons are differentially affected during neuropathic pain conditions, and emphasizes the importance of subpopulation specificity when targeting VTA DA neurons for treatment of neuropathic pain.
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PMID:Peripheral nerve injury-induced alterations in VTA neuron firing properties. 3168 30

The human norepinephrine transporter (hNET) is a member of the neurotransmitter/sodium symporter family, which also includes the neuronal monoamine transporters for serotonin (SERT) and dopamine (DAT). Its involvement in chronic pain and many neurological disorders underlies its pharmaceutical importance. Using the X-ray crystal structures of the human serotonin transporter (hSERT) (PDB 5I6X) and Drosophila melanogaster dopamine transporter (dDAT) (PDB 4M48 and PDB 4XPA) as templates, we developed molecular models for norepinephrine (NE) bound to its high affinity binding site (S1) in the hNET. Our model suggests that the S1 site for NE is deeply buried between transmembrane helices (TMHs) 1, 3, 6, and 8 and overlaps the binding site for leucine in the bacterial leucine transporter (LeuT) and dopamine (DA) in dDAT. Mutational studies identified the functional binding pocket for NE comprised residues A73, A77, N78, V148, N153, I156, G320, F329, N350, S420, G423, and M424, which all influenced NE affinity and/or transport. These effects support a NE-hNET docking model where A73, A77, G320, S420, G423, and M424 form H-bond interactions with NE, V148, I156, and F329 form hydrophobic interactions with NE, whereas N78 affects NE transport and N350 affects NE affinity and transport via an influence on the octahedral co-ordination of the Na1 + ion. Consistent with a conserved structure-function amongst sodium-dependent neurotransmitter transporters, S1 residues A73, A77 (G100 in hSERT), N78, V148 (I150 in hSERT), N153, G320, F329 (Y331 in d DAT), N350, and G423 are conserved in DAT and SERT, indicating they likely play conserved functional roles.
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PMID:Structure-Function of the High Affinity Substrate Binding Site (S1) of Human Norepinephrine Transporter. 3221 Aug 13