Desensitization and resensitization of adrenomedullin-sensitive receptor in rat mesangial cells.
Adrenomedullin is a potent adenylate cyclase activator and a vasodilatory peptide, that has anti-proliferative and apoptotic effects in rat mesangial cells. The present study was designed to determine the mechanisms of desensitization and resensitization of adrenomedullin-sensitive receptor in mesangial cells. Adrenomedullin caused a rapid desensitization of cAMP response evident within 5 min that was almost complete by 1 h of treatment. Pretreatment of cells with forskolin, that activates protein kinase-A by direct activation of adenylate cyclase, also caused adrenomedullin receptor desensitization. In addition, H89 [¿N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide, hydrochloride¿], a potent protein kinase-A inhibitor inhibited adrenomedullin-induced desensitization of cAMP response. Adrenomedullin also caused desensitization of isoproterenol- and epinephrine-mediated cAMP accumulation. Furthermore, adrenomedullin induced cross-desensitization of endothelin-stimulated inositol phosphate accumulation. The attenuated cAMP response of adrenomedullin was restored to original levels within 2 h of agonist removal. This resensitization response was blocked by treatment with okadaic acid, a protein phosphatase (protein phosphatase-1/protein phosphatase-2A) inhibitor, during the 2 h resensitization period, indicating that protein phosphatase-1/protein phosphatase-2A may be involved in the resensitization of the adrenomedullin-sensitive receptor. We demonstrate for the first time in rat mesangial cells that the adrenomedullin-sensitive receptor undergoes heterologous desensitization and resensitization, and that it likely involves protein kinase-A and protein phosphatase-1/protein phosphatase-2A, respectively.
Parameswaran
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N
Department of Physiology, Michigan State University, 103 Giltner Hall, 48824-1101, East Lansing, MI, USA.
Aiyar
N
N
Wu
H
H
Brooks
D P
DP
Nambi
P
P
Spielman
W S
WS
D053607:Adrenomedullin; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D019332:Endothelin-1; D007295:Inositol Phosphates; D010455:Peptides; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D014665:Vasodilator Agents; D053607:Adrenomedullin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases