Role of cyclic GMP and calcineurin in homologous and heterologous desensitization of natriuretic peptide receptor-A.
The natriuretic peptide receptor-A (NPR-A) mediates natriuretic, hypotensive, and antihypertrophic effects of natriuretic peptides through the production of cGMP. In pathological conditions such as heart failure, these effects are attenuated by homologous and heterologous desensitization mechanisms resulting in the dephosphorylation of the cytosolic portion of the receptor. In contrast with natriuretic peptide-induced desensitization, pressor hormone-induced desensitization is dependent on protein kinase C (PKC) stimulation and (or) cytosolic calcium elevation. Mechanisms by which PKC and Ca(2+) promote NPR-A desensitization are not known. The role of cGMP and of the cytosolic Ca(2+) pathways in NPR-A desensitization were therefore studied. In contrast with the activation of NPR-A by its agonist, activation of soluble guanylyl cyclases of LLC-PK1 cells by sodium nitroprusside also leads to a production of cGMP but without altering NPR-A activation. Consequently, cGMP elevation per se does not appear to mediate homologous desensitization of NPR-A. In addition, cytosolic calcium increase is required only for the heterologous desensitization pathway since the calcium chelator BAPTA-AM blocks only PMA or ionomycin-induced desensitization. Calcineurin inhibitors block the NPR-A guanylyl cyclase heterologous desensitization induced by ionomycin, suggesting an essential role for this Ca(2+)-stimulated phosphatase in NPR-A desensitization. In summary, the present report demonstrates that neither cGMP nor Ca(2+) cytosolic elevation cause NPR-A homologous desensitization. Our results also indicate for the first time a role for calcineurin in NPR-A heterologous desensitization.
Fortin
Yann
Y
Département de Pharmacologie, Faculté de Médecine, Université de Montréal, 2900 boul. Edouard-Montpetit, Pavillon Principal, V-437-1, Montréal, QC H3T 1J4, Canada.
De Léan
André
A
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism*; D018374:LLC-PK1 Cells; D009599:Nitroprusside / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D013552:Swine
D018160:Receptors, Cytoplasmic and Nuclear; D009599:Nitroprusside; D009320:Atrial Natriuretic Factor; D019703:Calcineurin; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D000071756:Soluble Guanylyl Cyclase; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP