The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase.
The signalling mechanism and cellular targets of the AT2 receptor are still unknown. We report that angiotensin II (Ang II) inhibits basal and atrial natriuretic peptide stimulated particulate guanylate cyclase (pGC) activity through AT2 receptors in rat adrenal glomerulosa and PC12W cells. This inhibition is blocked by the phosphotyrosine phosphatase (PTPase) inhibitor orthovanadate but not by the Ser/Thr phosphatase inhibitor okadaic acid, suggesting the involvement of a PTPase in this process. Moreover, Ang II induces a rapid, transient and orthovanadate sensitive dephosphorylation of phosphotyrosine containing proteins in PC12W cells. Our findings suggest that AT2 receptors signal through stimulation of a PTPase and that this mechanism is implicated in the regulation of pGC activity. This observation is also the first example of hormonal inhibition of basal pGC activity.
Bottari
S P
SP
Cardiovascular Department, Ciba-Geigy Ltd., Basel, Switzerland.
King
I N
IN
Reichlin
S
S
Dahlstroem
I
I
Lydon
N
N
de Gasparo
M
M
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D004988:Ethers, Cyclic / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular; D019319:Okadaic Acid; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014638:Vanadates / Q000494:pharmacology; D015384:Zona Glomerulosa / Q000378:metabolism
D004988:Ethers, Cyclic; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D019319:Okadaic Acid; D014638:Vanadates; D009320:Atrial Natriuretic Factor; D017027:Protein Tyrosine Phosphatases; D006162:Guanylate Cyclase