Kevin Erreger

Publications (15) View all

• Article: GLP-1 analog attenuates cocaine reward.

  D L Graham, K Erreger, A Galli, G D Stanwood
  Molecular psychiatry 10/2012; · 15.05 Impact Factor
• Article: Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder.

  Erica Bowton, Christine Saunders, Kevin Erreger, Dhananjay Sakrikar, Heinrich J Matthies, Namita Sen, Tammy Jessen, Roger J Colbran, Marc G Caron, Jonathan A Javitch, Randy D Blakely, Aurelio Galli
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  ABSTRACT: The neurotransmitter dopamine (DA) modulates brain circuits involved in attention, reward, and motor activity. Synaptic DA homeostasis is primarily controlled via two presynaptic regulatory mechanisms, DA D(2) receptor (D(2)R)-mediated inhibition of DA synthesis and release, and DA transporter (DAT)-mediated DA clearance. D(2)Rs can physically associate with DAT and regulate DAT function, linking DA release and reuptake to a common mechanism. We have established that the attention-deficit hyperactivity disorder-associated human DAT coding variant Ala559Val (hDAT A559V) results in anomalous DA efflux (ADE) similar to that caused by amphetamine-like psychostimulants. Here, we show that tonic activation of D(2)R provides support for hDAT A559V-mediated ADE. We determine in hDAT A559V a pertussis toxin-sensitive, CaMKII-dependent phosphorylation mechanism that supports D(2)R-driven DA efflux. These studies identify a signaling network downstream of D(2)R activation, normally constraining DA action at synapses, that may be altered by DAT mutation to impact risk for DA-related disorders.
  Journal of Neuroscience 04/2010; 30(17):6048-57. · 7.11 Impact Factor
• Article: Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux.

  Francesca Binda, Concetta Dipace, Erica Bowton, Sabrina D Robertson, Brandon J Lute, Jacob U Fog, Minjia Zhang, Namita Sen, Roger J Colbran, Margaret E Gnegy, Ulrik Gether, Jonathan A Javitch, Kevin Erreger, Aurelio Galli
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  ABSTRACT: The soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein syntaxin 1A (SYN1A) interacts with and regulates the function of transmembrane proteins, including ion channels and neurotransmitter transporters. Here, we define the first 33 amino acids of the N terminus of the dopamine (DA) transporter (DAT) as the site of direct interaction with SYN1A. Amphetamine (AMPH) increases the association of SYN1A with human DAT (hDAT) in a heterologous expression system (hDAT cells) and with native DAT in murine striatal synaptosomes. Immunoprecipitation of DAT from the biotinylated fraction shows that the AMPH-induced increase in DAT/SYN1A association occurs at the plasma membrane. In a superfusion assay of DA efflux, cells overexpressing SYN1A exhibited significantly greater AMPH-induced DA release with respect to control cells. By combining the patch-clamp technique with amperometry, we measured DA release under voltage clamp. At -60 mV, a physiological resting potential, AMPH did not induce DA efflux in hDAT cells and DA neurons. In contrast, perfusion of exogenous SYN1A (3 microM) into the cell with the whole-cell pipette enabled AMPH-induced DA efflux at -60 mV in both hDAT cells and DA neurons. It has been shown recently that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by AMPH and regulates AMPH-induced DA efflux. Here, we show that AMPH-induced association between DAT and SYN1A requires CaMKII activity and that inhibition of CaMKII blocks the ability of exogenous SYN1A to promote DA efflux. These data suggest that AMPH activation of CaMKII supports DAT/SYN1A association, resulting in a mode of DAT capable of DA efflux.
  Molecular pharmacology 08/2008; 74(4):1101-8. · 4.53 Impact Factor
• Article: Zinc inhibition of rat NR1/NR2A N-methyl-D-aspartate receptors.

  Kevin Erreger, Stephen F Traynelis
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  ABSTRACT: Zinc ions (Zn(2+)) are localized in presynaptic vesicles at glutamatergic synapses and released in an activity-dependent manner. Modulation of NMDA-type glutamate receptors by extracellular Zn(2+) may play an important role under physiological conditions and during pathologies such as ischaemia or seizure. Zn(2+) inhibits NMDA receptors containing the NR2A subunit with an IC(50) value in the low nanomolar concentration range. Here we investigate at the single-channel level the mechanism of high affinity Zn(2+) inhibition of recombinant NR1/NR2A receptors expressed in HEK293 cells. Zn(2+) reversibly decreases the mean single-channel open duration and channel open probability determined in excised outside-out patches, but has no effect on single-channel current amplitude. A parallel series of experiments demonstrates that lowering extracellular pH (increasing proton concentration) has a similar effect on NR1/NR2A single-channel properties as Zn(2+). Fitting the sequence of single-channel events with kinetic models suggests that the association of Zn(2+) with its binding site enhances proton binding. Modelling further suggests that protonated channels are capable of opening but with a lower open probability than unprotonated channels. These data and analyses are consistent with Zn(2+)-mediated inhibition of NMDA receptors primarily reflecting enhancement of proton inhibition.
  The Journal of Physiology 03/2008; 586(3):763-78. · 4.72 Impact Factor
• Article: Currents in response to rapid concentration jumps of amphetamine uncover novel aspects of human dopamine transporter function.

  Kevin Erreger, Christof Grewer, Jonathan A Javitch, Aurelio Galli
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  ABSTRACT: Amphetamine (AMPH) is a widely abused psychostimulant that acts as a substrate for the human dopamine transporter (hDAT). Using a piezoelectric rapid application system, we measured AMPH-induced currents mediated by hDAT. Whole-cell patch-clamp recordings in a heterologous expression system reveal that AMPH induces a rapidly activating and subsequently decaying inward current mediated by hDAT. We hypothesize that this transient inward current reflects a conformational change associated with substrate translocation. The AMPH-induced current strictly depends on extracellular Na+. Elevated intracellular Na+ has no effect on the peak AMPH-induced current amplitude but inhibits the steady-state current. In addition, elevated intracellular Na+ causes an overshoot outward current upon washout of AMPH that reflects hDAT locked in a Na+-exchange mode. Furthermore, elevated intracellular Na+ dramatically accelerates the recovery time from desensitization of the AMPH-induced current, revealing a new role for intracellular Na+ in promoting the transition to the hDAT "outward-facing" conformation. Ion substitution suggests that both extracellular and intracellular Cl- facilitate transporter turnover in contrast to the classical model of Cl- as a cotransported ion. We present an alternating-access model of hDAT function that accurately fits the main features of the experimental data. The model predicts that translocation of substrate occurs within milliseconds of substrate binding but that slow reorientation of the empty transporter is the rate-limiting factor for turnover. The model provides a framework for interpreting perturbations of hDAT activity.
  Journal of Neuroscience 02/2008; 28(4):976-89. · 7.11 Impact Factor