Neurotransmitter levels in brain are critical for normal brain function. Abnormal levels of neurotransmitter, resulting in inappropriate neural signaling, underlie a diverse set of brain disorders. For example, epilepsy, excitotoxic cell death, depression, and a number of conditions related to drug abuse are all associated with abnormal transmitter levels in brain. Neurotransmitter transporters are proteins, located on neurons and glia, that function in part to transport transmitter from the extracellular milieu into cells. As such, they play a central role in regulating synaptic signaling. Interestingly, we know that transporters themselves are subject to regulation by a number of signal transduction cascades, in part through a subcellular redistribution of the transporter. However, the mechanisms underlying this regulation, how the signal transduction pathways interact to control transporter expression, and the physiological relevance of transporter redistribution have yet to be thoroughly examined. The major goals of this application are to determine the signalling pathways that regulate trafficking of the predominant brain GABA transporter GAT1, and to evaluate the physiological relevance of this form of regulation.
Specific Aim 1 is to test the hypothesis that GAT1 redistribution occurs via the identical mechanisms that mediate the recycling of neurotransmitter- containing synaptic vesicles.
Specific Aim 2 is to test the hypothesis that signal transduction cascades which regulate GAT1 redistribution do so by direct transporter phosphorylation and subsequent alterations in rates of endocytosis.
Specific Aim 3 will examine the physiological relevance of the regulation of GAT1 redistribution by testing the hypothesis that alterations in GAT1 trafficking regulate GABAergic signaling in brain. These studies are important because they will (i) define the cellular machinery that participates in transporter trafficking; (ii) determine the signals that regulate transporter trafficking; (iii) determine the physiological relevance of this form of regulation; and (iv) provide data that could be useful in strategies aimed at regulating transporter function in the treatment of disorders related to abnormal transmitter levels.
| Moss, Fraser J; Imoukhuede, P I; Scott, Kimberly et al. (2009) GABA transporter function, oligomerization state, and anchoring: correlates with subcellularly resolved FRET. J Gen Physiol 134:489-521 |
| Hu, Jia; Quick, Michael W (2008) Substrate-mediated regulation of gamma-aminobutyric acid transporter 1 in rat brain. Neuropharmacology 54:309-18 |
