PT  - JOURNAL ARTICLE
AU  - Rima Mouawad
AU  - Yuan Li
AU  - Madhu B. Anand-Srivastava
TI  - Atrial Natriuretic Peptide-C Receptor-Induced Attenuation of Adenylyl Cyclase Signaling Activates Phosphatidylinositol Turnover in A10 Vascular Smooth Muscle Cells
AID  - 10.1124/mol.65.4.917
DP  - 2004 Apr 01
TA  - Molecular Pharmacology
PG  - 917--924
VI  - 65
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/65/4/917.short
4100  - http://molpharm.aspetjournals.org/content/65/4/917.full
SO  - Mol Pharmacol2004 Apr 01; 65
AB  - 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-ANP4-23 [des(Gln18,Ser19, Glu20,Leu21,Gly22)ANP4-23-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-ANP4-23-mediated stimulation of IP3 production. Forskolin (FSK), a stimulator of adenylyl cyclase, dibutyryl cAMP (db cAMP), and isoproterenol (ISO), a β-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-ANP4-23-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-ANP4-23-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-ANP4-23 and not ET-1-induced stimulation of IP3 production. These results indicate that ANP-C receptor activation by C-ANP4-23 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.