The dopamine transporter counter-transports potassium to increase the uptake of dopamine

The dopamine transporter (DAT) facilitates dopamine reuptake from the extracellular space, and thereby terminates neurotransmission and refills cellular stores of dopamine. DAT belongs to the neurotransmitter:sodium symporter (NSS) family, which includes similar transporters for serotonin, norepinephrine, and GABA. A hallmark of NSS proteins is their ability to utilize the energy stored in the inward-directed Na+ gradient to drive the uphill transport of substrate. Decades ago, it was shown that the serotonin transporter also counter-transports K+, but investigations of K+-coupled transport in other NSSs have been inconclusive. Here, we show that the Drosophila dopamine transporter (dDAT) counter-transports K+. We found that ligand binding to both dDAT and human DAT is inhibited by K+ and that the conformational dynamics of dDAT in K+ is highly divergent from both the apo- and Na+-bound conformations. Furthermore, we found that K+ increased dopamine uptake by purified dDAT reconstituted in liposomes, and we visualized, in real-time, Na+ and K+ fluxes in single proteoliposomes using fluorescent ion indicators. Our results expand on the fundamentals of dopamine transport and prompt a reevaluation of the impact of K+ on other NSSs, including whether K+ counter-transport is a common mechanism for this pharmacologically important protein family.

A case study on escitalopram induced QTc prolongation and adverse drug reaction

Antagonistic medication response (ADR) can be characterized as any toxic change which is suspected to be because of a medication, happens at dosages ordinarily utilized in man, requires treatment or decline in portion or shows alert later on the utilization of similar medication. Escitalopram is a medication which goes under the classification of particular serotonin reuptake inhibitors (SSRIs) (antidepressants). It is the S-enantiomer of the racemic subsidiary of citalopram, which specifically restrains the reuptake of serotonin with practically no impact on norepinephrine or dopamine reuptake. Practically all the antidepressants and antipsychotics have been connected to QT prolongation. In a patient with previously diagnosed congenital QTS, we present a drug-induced QT extension owing to the escitalopram overdose. A 15-year-old Caucasian woman was presented with an escalopram overdose after a suicide attempt. The patient has a lengthy QT period of torsade de point incidents. The patient was received and monitored in the telemetry facility. She proceeded to exhibit the persistently extended QT period after the resolution of torsades de punes. She was diagnosed with a congenital QT condition by the cardiology clinic. In this situation, an escitalopram overdose is seen to trigger an immediate QT extension for a patient who has congenital LQTS and the value of an electrocardiogram before SSRIs are started, particularly for those at high risk of QT prolongation.

Bupropion in the treatment of postural orthostatic tachycardia syndrome (POTS): a single-center experience

Postural orthostatic tachycardia syndrome (POTS) is estimated to impact millions of people each year. However, there is no established gold standard for its treatment. Bupropion is a norepinephrine and a dopamine reuptake inhibitor and has been implicated as a potential treatment for POTS. We performed a non-randomized retrospective chart review on 47 patients with POTS with statistical analysis evaluating for significant findings including reduced orthostasis and improvement of symptoms with the use of bupropion. Bupropion was not associated with a statistically significant improvement in orthostatic vitals but there was an overall reduction in reported syncope. While the use of bupropion does not show a statistically significant impact on orthostatic vitals in patients with POTS, it did show a degree of improvement in syncope and as such might be useful in patients with syncope-predominant POTS.

Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors

SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.