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Atrial Natriuretic Peptide-C Receptor-Induced Attenuation of Adenylyl Cyclase Signaling Activates Phosphatidylinositol Turnover in A10 Vascular Smooth Muscle Cells

Department of Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada H3C 3J7

Atrial natriuretic peptide (ANP)-C receptor activation has been shown to inhibit adenylyl cyclase (AC) activity as well as to stimulate phospholipase C (PLC) signaling pathways. The present studies were undertaken to investigate whether ANP-C receptor-mediated decreased cAMP levels contribute to the activation of PLC signaling. C-ANP_4-23 [des(Gln¹⁸,Ser¹⁹, Glu²⁰,Leu²¹,Gly²²)ANP_4-23-NH₂], a ring-deleted peptide of ANP that interacts specifically with ANP-C receptor, stimulated inositol 1,4,5-tris-phosphate (IP₃) production (PLC activity) in A10 vascular smooth muscle cells in a concentration- and time-dependent manner. The maximal stimulation observed was about 75% at 2 h of treatment, with an apparent EC₅₀ of about 20 to 30 nM. Pertussis toxin treatment of the cells completely abolished the C-ANP_4-23-mediated stimulation of IP₃ production. Forskolin (FSK), a stimulator of adenylyl cyclase, dibutyryl cAMP (db cAMP), and isoproterenol (ISO), a -adrenergic agonist that stimulates adenylyl cyclase activity and cAMP levels, inhibited IP₃ production by about 35, 30, and 50%, respectively, whereas dideoxyadenosine (DDA), an inhibitor of adenylyl cyclase activity, and oxotremorine stimulated IP₃ production by about 90 and 80%, respectively, in these cells, suggesting a functional interaction between these two signaling pathways. Treatment of the cells with antisense oligonucleotide of ANP-C receptor that attenuated ANP-C receptor-mediated inhibition of adenylyl cyclase resulted in a complete attenuation of C-ANP_4-23-induced stimulation of IP₃ formation, whereas FSK, db cAMP, and ISO-mediated decrease and oxotremorine and endothelin-1 (ET-1)-induced increase in IP₃ production was not affected by this treatment. Furthermore, C-ANP_4-23-induced increase in IP₃ formation was significantly potentiated by DDA and inhibited by FSK and db cAMP, whereas ET-1-induced increase in IP₃ production was not affected by FSK. In addition, N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H-89), an inhibitor of protein kinase A, completely abolished C-ANP_4-23 and not ET-1-induced stimulation of IP₃ production. These results indicate that ANP-C receptor activation by C-ANP_4-23 and resulting decrease in cAMP levels may be responsible for the activation of phosphatidylinositol (PI) turnover signaling, suggesting a cross-talk between ANP-C receptor-mediated adenylyl cyclase and PLC signaling pathways.

Address correspondence to: Dr. Madhu B. Anand-Srivastava, Department of Physiology, Faculty of Medicine, University of Montreal, C.P. 6128, succ. Centre-ville, Montreal, Quebec, Canada, H3C 3J7. E-mail: anandsrm{at}physio.umontreal.ca

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