Abstract:
:The type 1B angiotensin II (AT1B) receptor cloned from rat kidney was stably expressed in Chinese hamster ovary cells. The stably expressed receptor was characterized by radioligand binding studies and functional coupling to inositol 1,4,5-triphosphate (IP3) formation. Exposure of cells expressing the AT1B receptor to angiotensin II (Ang II) resulted in a rapid and dose-dependent homologous desensitization of receptor-mediated production of IP3, with an essentially complete desensitization at an agonist concentration > 10 nmol/L. Binding studies revealed no significant change in the number of AT1B receptors in transfected cells exposed to 1 nmol/L Ang II, whereas exposure to 100 nmol/L Ang II caused a rapid decrease of cell surface receptors, with a 75% loss of receptor number seen at 1 hour. Rapid desensitization occurred in the absence of receptor internalization. Blockade of receptor internalization with concanavalin A had at most only a slight effect on the agonist-induced desensitization. This indicates that factors other than internalization are chiefly responsible for the rapid agonist-induced desensitization. Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, caused rapid desensitization of the receptor-mediated IP3 response. Neither tyrosine kinase inhibitors nor a protein kinase A activator affected the receptor-mediated IP3 response. The specific PKC inhibitor GF109203X or PKC depletion by prolonged treatment with 1 mumol/L PMA completely blocked the PMA-dependent desensitization. Desensitization evoked by a low Ang II agonist concentration (1 nmol/L) was reversed by the PKC-specific inhibitor GF109203X or PKC depletion, whereas the desensitizing effect at a high agonist concentration (100 nmol/L) is only partially prevented by PKC inhibitory treatment. These results demonstrate that PKC plays a crucial role in the desensitization of the AT1B receptor. They also suggest that receptor internalization and an additional PKC-independent pathway also contribute to desensitization of the AT1B receptor in transfected cells.
journal_name
Circ Resjournal_title
Circulation researchauthors
Tang H,Shirai H,Inagami Tdoi
10.1161/01.res.77.2.239subject
Has Abstractpub_date
1995-08-01 00:00:00pages
239-48issue
2eissn
0009-7330issn
1524-4571journal_volume
77pub_type
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