Project Details


The long term goal of our research is to understand the mechanism of signal
transduction by neuropeptide receptors. Substance-K (neurokinin-A)
receptors play important roles in both normal and pathological processes,
including memory retention and rheumatoid arthritis [l, 2, 3]. The goal of
the research proposed here is to determine structure-function relationships
of neuropeptide receptors using Neurokinin A receptor as a model system for
neuropeptide receptors, which have seven hydrophobic membrane spanning
regions. Following ligand binding, neuropeptide receptors couple with
G-proteins to transduce their signals.
A key breakthrough in analyzing structure-function is the cloning of the
receptor. The human Neurokinin A receptor has been cloned by us and will
be used in this analysis. Specific aims are 1) To determine functional
domains of the substance-K receptor involved with G-protein interaction by
producing chimeras between the neurokinin A receptor and the beta2-
adrenergic receptor which utilize different G-proteins. Precedence from
the adrenergic and muscarinic receptor systems will guide the choice of
domains to be swapped. 2) To determine the role of post-translational
modification of the Neurokinin A receptor. a) There are potential
myristylation and palmitoylation sites on the Neurokinin A receptor. The
use and importance of these sites will be analyzed by metabolic labelling
experiments and site directed mutagenesis. b) The response to neurokinin A
is rapidly desensitized. In the adrenergic system, desensitization has
been shown to controlled by phosphorylation of the C-terminal tail. The
role of phosphorylation of the C-terminal tail of the Neurokinin A receptor
will be analyzed by in vivo labelling with 32p and by deletion mutagenesis
of the C-terminal tail.

A concise understanding of the sites important in the interaction between
neuropeptide receptors and their transducing proteins (G-proteins) is
necessary for understanding the mechanism of signal transduction by
neuropeptide receptors. The site of G-protein interaction and the role of
post-translational modifications of the Neurokinin A receptor are keys in
understanding the mechanism of stimulation or desensitization of the
response to Neurokinin A, important concepts in normal regulation of the
proper receptor function. The understanding of mechanism of signal
transduction by these receptors may lead to more potent drugs for treating
diseases such as rheumatoid arthritis and for analysis of memory retention
induced b Neurokinin A.
Effective start/end date2/1/921/31/95


  • Cell Biology


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