Insights into the Regulation of the Glycine Transporter 1 (GlyT1)

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DESCRIPTION (provided by applicant): Glycine is the major inhibitory neurotransmitter in the brainstem and spinal cord, where it functions at specific strychnine-sensitive glycine receptors. In addition, glycine participates in excitatory neurotransmission as an essential co-agonist of glutamate at N-methyl-D-aspartate (NMDA) receptor containing synapses; therefore, NMDA receptor activation is tightly modulated by the activity of the plasma membrane glycine transporter 1 (GlyT1) present in presynaptic neurons and neighboring glial cells. Altered numbers of functional NMDA receptors have been suggested to underlie some of the symptoms in schizophrenia, primarily in cognitive functions. The GlyT1 has been the main target for drug development in schizophrenia; however, how the transporter is regulated remains poorly understood. It is known for several members of the monoamine transporter family that transport activity is linked to activation of Protein Kinase C (PKC); however, the mechanism of regulation is controversial or unknown in the brain. Given the strength of clinical and pharmacological data suggesting glutamate receptor dysfunction in schizophrenia and the role of the glycine transporter as a potential drug target, in this study our goal is to characterize the regulatory mechanism of the GlyT1 using two expression systems: (a) mouse GlyTIa expressed in model cell lines (HeLa and Porcine Aortic Endothelial cells, PAE) and (b) endogenous GlyT1 in primary cultures from rat hippocampus. Based on preliminary data from our laboratory that suggest enhanced PKC-dependent ubiquitination and endocytosis obtained by expressing GlyT1 in HeLa cells, we hypothesize that PKC activation results in GlyT1 ubiquitination and down-regulation in the brain, contributing to the regulation of the glycine transporter. This research will offer new potential pharmacological targets to treat neurological disorders, such as schizophrenia.