The Role of Ceramide Kinase in Neurosecretion

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DESCRIPTION: (provided by the applicant) Chronic drug use leads to changes in neuronal functioning that ultimately result in addiction and tolerance. Like other forms of neuronal plasticity, drug-induced adaptations include modifications of synaptic efficacy. An understanding of synaptic functioning at a molecular level is therefore a crucial first step towards identifying the molecular changes that produce addiction and tolerance. Research into the molecular basis of synaptic transmission has focused largely on proteins of the synapse. However, as in other cellular processes, lipids also play a crucial role. The larger goal of this project is to elucidate the role of sphingolipids in neurotransmitter secretion, a role suggested by the presence of a ceramide (N-acyl sphingosine) kinase on synaptic vesicles. cDNAs encoding a ceramide kinase of any kind have yet to be identified. This Stage I project aims to 1) isolate cDNAs encoding brain ceramide kinase and 2) to identify the tissue expression patterns and intracellular location of brain ceramide kinase. This work will lay the foundation for biochemical and genetic studies of the role of ceramide kianse, its substrate and its product in neurotransmission and how changes in its activity contribute to synaptic plasticity.