Mechanisms involved in desensitization of particulate guanylyl cyclase in human airway smooth muscle: the role of protein kinase C.
We recently showed that cultured human airway smooth muscle cells (HASMC) express both soluble and particulate guanylyl cyclases (GC) and that long term treatment with atrial natriuretic peptide (ANP) causes homologous desensitization of particulate GC. Here we determine if protein kinase C (PKC) activation would desensitize particulate GC and probe the role of PKC in particulate GC desensitization. Pretreatment of HASMC with phorbol 12-myristate 13-acetate (PMA), a PKC activator led to time and concentration-dependent desensitization of ANP-stimulated cGMP accumulation. GF109203X, a selective PKC inhibitor, blocked the PMA-induced desensitization, but did not block ANP-induced desensitization. In addition, desensitization by PMA and ANP showed an additive effect. These results suggest that PKC activation can desensitize particulate GC but that the desensitization induced by ANP is PKC-independent.
Hamad
A M
AM
Department of Respiratory Medicine, City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom. alan.knox@nottingham.ac.uk
Knox
A J
AJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010704:Phorbols / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D012995:Solubility; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013997:Time Factors
D007211:Indoles; D008301:Maleimides; D010704:Phorbols; D010726:Phosphodiesterase Inhibitors; D009320:Atrial Natriuretic Factor; D011493:Protein Kinase C; D006162:Guanylate Cyclase; D006152:Cyclic GMP; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; D015056:1-Methyl-3-isobutylxanthine; C033085:phorbol