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Am J Physiol Cell Physiol 279: C1978-C1985, 2000;
0363-6143/00 $5.00
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Vol. 279, Issue 6, C1978-C1985, December 2000

Protein kinase C contributes to desensitization of ANG II signaling in adult rat cardiac fibroblasts

J. Gary Meszaros1, Robert Raphael1, Francisco M. Lio1, and Laurence L. Brunton1,2

Departments of 1 Pharmacology and 2 Medicine, University of California, San Diego, School of Medicine, La Jolla, California 92093-0636

We have studied Gq-linked ANG II signaling [inositol phosphate (IP) accumulation, Ca2+ mobilization] in primary cultures of rat cardiac fibroblasts (CFs) and have found that ANG II initiates a protein kinase C (PKC)-mediated negative feedback loop that rapidly terminates the ANG II response. Pharmacological inhibition of PKC by staurosporine and GF-109203X doubled IP production over that achieved in response to ANG II alone. Inhibition of PKC also led to larger Ca2+ transients in response to ANG II, suggesting that Ca2+ mobilization was proportional to Gq-phospholipase C-IP3 activity under the conditions studied. Depletion of cellular PKC by overnight treatment with phorbol 12-myristate 13-acetate (PMA) similarly augmented ANG II-induced IP production. Acute activation of PKC by PMA halved IP formation, with an EC50approx 1 nM; 4alpha -PMA was inactive. Time course data demonstrated that ANG II-mediated IP production fully desensitized within 30 s; PKC inhibition reduced the rate and extent of this desensitization. In cells desensitized to ANG II, a purinergic agonist still mobilized intracellular Ca2+, indicating that desensitization was homologous. The ANG II-induced Ca2+ signal was fully resensitized within 30 min. The data demonstrate that a large portion of the IP-Ca2+ responses of rat CFs to ANG II are short-lived because of rapid, PKC-mediated desensitization.

AT1 receptor; angiotensin II; purinergic receptor; inositol phosphates; intracellular calcium


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