Project: Research project

Project Details


The applicant's long term goals are to study the regulation of neuronal
transmission in the central nervous system and to understand the role of
pharmacological agents in modifying neuronal transmission. Specifically,
the goals are to study the mechanisms of catecholamine storage, release
and reuptake within the presynaptic neuron. Catecholaminergic reuptake into presynaptic neurons following synaptic
release is the primary mechanism of terminating the response to
catecholamines at post-synaptic receptors. Specific reuptake of
norepinephrine, dopamine, and serotonin into the presynaptic neuron is
achieved by the high affinity, energy-dependent co-transport of the
neurotransmitter along with sodium ions through specific membrane-bound
proteins. The importance of catecholamine uptake proteins in our society is best
exemplified by the impact of various competitive inhibitors of these
proteins. These inhibitors include cocaine, amphetamine, and the tri-
cyclic antidepressants. The stimulatory action and the abuse potential of
these drugs is related directly to their ability to bind and block
catecholamine uptake sites. To study the pharmacology of these inhibitory agents, it is necessary to
isolate the class of transporter proteins that they inhibit from other
proteins involved in catecholamine metabolism. Protein purification
strategies have failed to provide structural information regarding these
transport proteins. The molecular cloning of the catecholamine
transporters is essential for understanding the pharmacology of their
action and their inhibition by drugs of abuse. Because the catecholamine uptake transporter can be expressed and can
concentrate catecholamines into heterogenous cells, it is ideally suited
for some expression cloning techniques. Frog oocyte assays will be used
initially to define mRNA's encoding the transporter and to characterize
parameters of uptake. cDNA libraries, enriched for the catecholamine
transporter clones, will be expressed to high level in eukaryotic cells.
Mammalian cloning systems will be used to identify single cells expressing
the cDNA for the catecholamine uptake transporter. Recovery of the
transporter cDNA from these cells will allow complete sequence
determination, and characterization of the transporter protein itself.
Expression of the cDNA in heterogenous cells will allow pharmacological
investigation of both catecholamine uptake and its inhibition by cocaine.
Effective start/end date9/30/908/31/92


  • National Institutes of Health


  • Medicine(all)


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