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Molecular mechanisms underlying transient cGMP signals
Author(s) -
Rich Thomas C,
Britain Andrea L,
Zhu Bing,
Henesy Michelle B
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.888.3
Subject(s) - desensitization (medicine) , phosphodiesterase , calcineurin , cgmp specific phosphodiesterase type 5 , medicine , chemistry , endocrinology , atrial natriuretic peptide , stimulation , receptor , phosphodiesterase 3 , biology , enzyme , erectile dysfunction , biochemistry , transplantation
We have examined the relationships between natriuretic peptide receptor‐A (NPR‐A) desensitization and phosphodiesterase (PDE) activity in regulating ANP‐induced cGMP signals in a murine Leydig tumor (MA‐10) cells. We have observed that prolonged exposure to ANP leads to an increase and subsequent decrease in cGMP levels. This suggests that following exposure to ANP NPR‐A desensitizes or the rate of cGMP hydrolysis increases with time. We have presented data suggesting that calcineurin underlies the desensitization of NPR‐A in these cells. We have also measured PDE activity and cGMP accumulation in the presence of a variety of type‐specific PDE inhibitors and found that PDE5 is primarily responsible for the hydrolysis of cGMP. In addition, we have observed an ANP‐dependent increase in PDE5 activity. These data suggest that the decrease in cGMP levels is due to both calcineurin‐mediated desensitization of NPR‐A and an ANP‐induced increase in PDE5 activity. To discern the relative roles of desensitization and PDE activity we have developed a quantitative model of the cGMP signaling pathway. Simulations of the model suggest that both calcineurin‐mediated desensitization of NPRA and ANP‐induced stimulation of PDE5 activity are critical processes in the shaping of cGMP signals in MA‐10 cells. Supported by AHA 0715101B, 0335084N, and NIH HL074278.