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Thiol-dependent redox modulation of soluble guanylyl cyclase

BMC Pharmacology
Springer (Biomed Central Ltd.)
Publication Date
DOI: 10.1186/1471-2210-9-s1-s4
  • Oral Presentation
  • Medicine

Abstract BioMed Central Page 1 of 1 (page number not for citation purposes) BMC Pharmacology Open AccessOral presentation Thiol-dependent redox modulation of soluble guanylyl cyclase Padma Baskaran, Samba Couloubaly, Jamila Hedhli, Chirag Patel, Smita Shukla and Annie Beuve* Address: Department of Pharmacology and Physiology, New Jersey Medical School (UMDNJ), Newark, NJ, USA Email: Annie Beuve* - [email protected] * Corresponding author Background Following prolonged exposure to NO, soluble guanylyl cyclase (sGC) becomes desensitized and fails to respond to additional NO stimulation. We showed that sGC is desensitized by S-nitrosylation in vitro, in primary smooth muscle cells (SMC) and in tissues and identified two cysteines (Cys) targeted by this post-translational modifi- cation that are involved in sGC desensitization [1]. We recently discovered that nitroglycerin (GTN) induces S- nitrosylation of sGC. We also showed that chronic treat- ment with GTN or acute treatment with S-nitroso-cysteine (CSNO), which lead to impaired relaxation in vivo, were accompanied by decreased GTN- or NO-stimulated cGMP production and characterized by strong S-nitrosylation of sGC. These observations suggested that desensitization of sGC by S-nitrosylation could be a mechanism of tolerance [2]. Based on observations by others that chronic GTN treatment increases ROS species and that oxidants expo- sure of cells impaired sGC response to NO, we hypothe- size that desensitization of sGC by redox-dependent modification of its Cys is a mechanism underlying the loss of vascular reactivity in some oxidative vascular diseases. Results and discussion We have now identified two additional Cys by Mass Spec that are, at least in vitro, S-nitrosylated. Mutational analy- sis of these Cys-sGC mutants seems to indicate that these four Cys are differentially modified upon exposure to oxi- dative or nitrosative stress. For example, β1C122 located in the heme-binding domain appears to be b

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