Natriuretic peptides increase cAMP production in human thyrocytes via the natriuretic peptide clearance receptor (NPR-C).
The relationship between natriuretic peptides and adenylyl cyclase/cAMP signal transduction has generally been shown to be an inhibitory one, mediated via the NPR-C receptor coupled to adenylyl cyclase by inhibitory G proteins (Gi). In the present studies, we have investigated the modulation of cAMP by natriuretic peptides in a long-term culture of human thyroid cells. Competition of [125I] rat ANF binding to human thyrocytes (HTU-5) by rat ANF (99-126) and by the NPR-C-specific analog C-ANF (4-23) indicated that greater than 97% of the ANF binding sites on HTU-5 cells are of the NPR-C type. However, rather than inhibiting intracellular cAMP in these cells, ANF increased maximal cAMP to 200-300% of control value. The ANF-induced increase in cAMP was duplicated by C-ANF (4-23). Basal cAMP content was reduced, and the response to ANF was abolished when the cells were grown in low (0.5%) serum without the addition of pituitary and hypothalamic extracts. CNP-22 also increased cAMP above control in HTU-5 cells identically to ANF. Neither ANF nor C-ANF (4-23) had any effect on cAMP in a culture of rat aortic smooth muscle cells. These results provide the first evidence for a positive effect of natriuretic peptides on cAMP mediated through the NPR-C, suggesting the possibility of an alternative mode of signaling by this receptor subtype.
Sellitti
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Department of Medicine, Divisions of Endocrinology and Nephrology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, A 3060, Bethesda, MD 20814-4799, USA.
Perrella
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G
Doi
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Curcio
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D009320:Atrial Natriuretic Factor / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase; D006801:Humans; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*
D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C; D006152:Cyclic GMP