Plasma membrane transporters control the active reuptake of neurotransmitters that mediate chemical signaling in the nervous system. Biogenic amine neurotransmitters (i.e. norepinephrine, NE) play a role in a number of physiological functions including autonomic regulation, locomotion, and complex behaviors such as attention and reward. By terminating these chemical signals, monoamine transporters are critical to the efficient function of the nervous system. The NE system has been implicated in a range of mood and anxiety disorders and the development of drugs such as reboxetine specifically targeting the norepinephrine transporter (NET)are promising therapeutic agents. NET is also a target for drugs of abuse such as the psychostimulants cocaine and amphetamine (AMPH). At present there are few reports of high resolution measures of intrinsic transporter function. We propose to use NET currents as one measure of transporter activity, including real-time recordings of unitary transporter currents in excised patches. Transporter currents and substrate flux will be used as functional readouts for transporter regulation by AMPH and a range of other modulators. This work will characterize AMPH regulation of monoamine transporter intrinsic function and regulation, and will also be important in building a framework in which to interpret changes caused by physiological modulators, drugs of abuse, and therapeutic agents.
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| Erreger, Kevin; Grewer, Christof; Javitch, Jonathan A et al. (2008) Currents in response to rapid concentration jumps of amphetamine uncover novel aspects of human dopamine transporter function. J Neurosci 28:976-89 |
| Binda, Francesca; Dipace, Concetta; Bowton, Erica et al. (2008) Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux. Mol Pharmacol 74:1101-8 |
