Protein kinase C contributes to desensitization of ANG II signaling in adult rat cardiac fibroblasts |
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Authors: | Meszaros J G Raphael R Lio F M Brunton L L |
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Affiliation: | Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, California 92093-0636, USA. |
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Abstract: | We have studiedGq-linked ANG II signaling [inositol phosphate (IP)accumulation, Ca2+ mobilization] in primary cultures ofrat cardiac fibroblasts (CFs) and have found that ANG II initiates aprotein kinase C (PKC)-mediated negative feedback loop that rapidlyterminates the ANG II response. Pharmacological inhibition of PKC bystaurosporine and GF-109203X doubled IP production over that achievedin response to ANG II alone. Inhibition of PKC also led to largerCa2+ transients in response to ANG II, suggesting thatCa2+ mobilization was proportional toGq-phospholipase C-IP3 activity underthe 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 PMAhalved IP formation, with an EC501 nM; 4-PMA wasinactive. Time course data demonstrated that ANG II-mediated IPproduction fully desensitized within 30 s; PKC inhibition reducedthe rate and extent of this desensitization. In cells desensitized toANG II, a purinergic agonist still mobilized intracellularCa2+, indicating that desensitization was homologous. TheANG II-induced Ca2+ signal was fully resensitized within 30 min. The data demonstrate that a large portion of theIP-Ca2+ responses of rat CFs to ANG II are short-livedbecause of rapid, PKC-mediated desensitization. |
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