NO-sensitive guanylyl cyclase and NO-induced feedback inhibition in cGMP signaling.
Most effects of the signaling molecule nitric oxide (NO) are mediated by the stimulation of NO-sensitive guanylyl cyclase (GC) and the subsequent intracellular increase in cGMP. Two isoforms of NO-sensitive GC have been identified to date that share regulatory properties but differ in their subcellular localization; the more ubiquitously expressed alpha1beta1 heterodimer, and the alpha2beta1 isoform mainly expressed in brain. New activators of NO-sensitive GC have been identified which may have beneficial pharmacological effects in cardiovascular diseases. In intact cells, NO-induced cGMP signaling not only depends on cGMP formation but is also critically determined by the activity of the enzyme responsible for cGMP degradation, e.g. phosphodiesterase 5 (PDE5). Sustained activation of PDE5 by cGMP has been identified as the mechanism responsible for the recently observed feedback inhibition within NO/cGMP signaling. Moreover, tuning of PDE5 activity may also represent a regulatory link to mediate cross talk between NO-induced and natriuretic peptide-induced cGMP signaling in general.
Mullershausen
Florian
F
Institut fuer Pharmakologie und Toxikologie, Medizinische Fakultaet MA N1, Ruhr-Universitaet Bochum, Universitaetsstr 150, 44789 Bochum, Germany.
Koesling
Doris
D
Friebe
Andreas
A
D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000494:pharmacology*; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D006152:Cyclic GMP