Project Details
Description
The objective of the proposed research is to elucidate the molecular
mechanisms involved in desensitization of adrenergic receptors by
catecholamines and other agonists. Previous studies in isolated cells in
culture have documented several distinct steps involved in the overall
process of desensitization; however, the molecular nature of the changes
involved remains unknown. Recent studies indicate the widespread
occurrence and clinical significance of desensitization of adrenergic
receptors in various human tissues, in particular heart, lung, leukocytes,
and lymphocytes. Furthermore, preliminary studies suggest that the
cellular mechanisms involved in desensitization in these tissues in intact
animals are probably similar to those demonstrated in cultured cells.
Thus, further studies of the molecular mechanisms involved in
desensitization in cultured cell lines, which are more amenable to study,
will likely lead to information that will be of relevance to understanding
desensitization in various tissues in man. The proposed studies will use recently developed techniques involving
short-time assays with intact cells to study the molecular events involved
in desensitization of beta-adrenergic receptors (BAR). These assays will
further investigate the involvement of internalization of BAR in
desensitization of cultured human astrocytoma cells (1321N1) and will be
used to identify inhibitors of the various biochemical reactions involved
in desensitization. The possible involvement of the cytoskeletal system,
cyclic-AMP-independent phosphorylation, transmethylation reactions, and
various ions and ion gradients in desensitization will be investigated.
Other studies will attempt to develop broken cell systems in which
biochemical studies of receptor modification can be carried out. Finally,
the intact cell binding techniques developed for study of BAR will also be
applied to a study of the likely involvement of similar changes in
alpha-1-adrenergic receptors on intact cells in culture.
mechanisms involved in desensitization of adrenergic receptors by
catecholamines and other agonists. Previous studies in isolated cells in
culture have documented several distinct steps involved in the overall
process of desensitization; however, the molecular nature of the changes
involved remains unknown. Recent studies indicate the widespread
occurrence and clinical significance of desensitization of adrenergic
receptors in various human tissues, in particular heart, lung, leukocytes,
and lymphocytes. Furthermore, preliminary studies suggest that the
cellular mechanisms involved in desensitization in these tissues in intact
animals are probably similar to those demonstrated in cultured cells.
Thus, further studies of the molecular mechanisms involved in
desensitization in cultured cell lines, which are more amenable to study,
will likely lead to information that will be of relevance to understanding
desensitization in various tissues in man. The proposed studies will use recently developed techniques involving
short-time assays with intact cells to study the molecular events involved
in desensitization of beta-adrenergic receptors (BAR). These assays will
further investigate the involvement of internalization of BAR in
desensitization of cultured human astrocytoma cells (1321N1) and will be
used to identify inhibitors of the various biochemical reactions involved
in desensitization. The possible involvement of the cytoskeletal system,
cyclic-AMP-independent phosphorylation, transmethylation reactions, and
various ions and ion gradients in desensitization will be investigated.
Other studies will attempt to develop broken cell systems in which
biochemical studies of receptor modification can be carried out. Finally,
the intact cell binding techniques developed for study of BAR will also be
applied to a study of the likely involvement of similar changes in
alpha-1-adrenergic receptors on intact cells in culture.
| Status | Finished |
|---|---|
| Effective start/end date | 9/1/85 → 8/31/90 |
Funding
- National Institutes of Health
ASJC
- Medicine(all)
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