Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In squamous cell carcinoma, the levels of nitric oxide (NO) derived from inducible NO synthase (iNOS) and prostaglandin E2 (PGE2) derived from cyclooxygenase-2 (COX-2) originated from tumor cells or tumor-associated inflammatory cells have been reported to correlate with tumor growth, metastasis, and angiogenesis. The present study examined the role of the iNOS signaling pathway in PGE2-mediated tumor invasiveness and proliferation in squamous cell carcinoma, A431, and SCC-9 cells. Cell invasion and proliferation promoted by PGE2 were blocked by iNOS silencing RNA or iNOS/guanylate cyclase (GC) pharmacological inhibition. Consistently, iNOS-GC pathway inhibitors blocked mitogen-activated protein kinase-ERK1/2 phosphorylation, which was required to mediate PGE2 functions. In vivo, in A431 cells implanted in nude mice, GC inhibition also decreased the tumor proliferation index and ERK1/2 activation. PGE2 effects were confined to the selective stimulation of the EP2 receptor subtype, leading to epidermal growth factor receptor (EGFR) transactivation via protein kinase A (PKA) and c-Src activation. EP2-mediated ERK1/2 activation and cell functions were abolished by inhibitors of PKA, c-Src, and EGFR, as well as by inhibiting iNOS pathway. Silencing of iNOS also impaired EGFR-induced ERK1/2 phosphorylation. These results indicate that iNOS/GC signaling is a downstream player in the control of EP2/EGFR-mediated tumor cell proliferation and invasion.
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PMID:EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways. 1738 45

The present experiments were designed to test the hypothesis that prostaglandin (PG) E(2) causes vasodilatation through activation of endothelial NO synthase (eNOS). Aortic rings from mice with targeted deletion of eNOS and E-prostanoid (EP) receptors were used for contraction studies. Blood pressure changes in response to PGE(2) were measured in conscious mice. Single doses of PGE(2) caused concentration-dependent relaxations during contractions to phenylephrine (EC(50)=5*10(-8) mol/L). Relaxation after PGE(2) was absent in rings without endothelium and in rings from eNOS(-/-) mice and was abolished by N(G)-nitro-l-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H(1,2,4)-oxadiazolo-[4,3-a]quinoxalin-1-one. In PGE(2)-relaxed aortic rings, the cGMP content increased significantly. PGE(2)-induced relaxations were abolished by the EP4 receptor antagonist AE3-208 (10(-8) mol/L) and mimicked by an EP4 agonist (AE1-329, 10(-7) mol/L) in the presence of endothelium and eNOS only. Relaxations were attenuated significantly in rings from EP4(-/-) mice but normal in EP2(-/-). Inhibitors of the cAMP-protein kinase A pathway attenuated, whereas the inhibitor of protein phosphatase 1C, calyculin (10(-8) mol/L), abolished the PGE(2)-mediated relaxation. In aortic rings, PGE(2) dephosphorylated eNOS at Thr(495). Chronically catheterized eNOS(-/-) mice were hypertensive (137+/-3.6 mm Hg, n=13, versus 101+/-3.9 mm Hg, n=9) and exhibited a lower sensitivity of blood pressure reduction in response to PGE(2) compared with wild-type mice. There was no difference in the blood pressure response to nifedipine. These findings show that PGE(2) elicits EP4 receptor-mediated, endothelium-dependent stimulation of eNOS activity by dephosphorylation at Thr(495) resulting in guanylyl cyclase-dependent vasorelaxation and accumulation of cGMP in aortic rings.
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PMID:Prostaglandin E2 induces vascular relaxation by E-prostanoid 4 receptor-mediated activation of endothelial nitric oxide synthase. 1763 57

Lubiprostone is a chloride (Cl(-)) channel activator derived from prostaglandin E1 and used for managing constipation. In addition, lubiprostone affects the activity of gastrointestinal smooth muscles. Interstitial cells of Cajal (ICCs) are pacemaker cells that generate slow-wave activity in smooth muscles. We studied the effects of lubiprostone on the pacemaker potentials of colonic ICCs. We used the whole-cell patch-clamp technique to determine the pacemaker activity in cultured colonic ICCs obtained from mice. Lubiprostone hyperpolarized the membrane and inhibited the generation of pacemaker potentials. Prostanoid EP1, EP2, EP3, and EP4 antagonists (SC-19220, PF-04418948, 6-methoxypyridine-2-boronc acid N-phenyldiethanolamine ester, and GW627368, respectively) did not block the response to lubiprostone. L-NG-nitroarginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase) and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, an inhibitor of guanylate cyclase) did not block the response to lubiprostone. In addition, tetraethylammonium (TEA, a voltage-dependent potassium [K(+)] channel blocker) and apamin (a calcium [Ca(2+)]-dependent K(+) channel blocker) did not block the response to lubiprostone. However, glibenclamide (an ATP-sensitive K(+) channel blocker) blocked the response to lubiprostone. Similar to lubiprostone, pinacidil (an opener of ATP-sensitive K(+) channel) hyperpolarized the membrane and inhibited the generation of pacemaker potentials, and these effects were inhibited by glibenclamide. These results suggest that lubiprostone can modulate the pacemaker potentials of colonic ICCs via activation of ATP-sensitive K(+) channel through a prostanoid EP receptor-independent mechanism.
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PMID:Effects of lubiprostone on pacemaker activity of interstitial cells of cajal from the mouse colon. 2517 67

Nephrogenic diabetes insipidus (NDI) is characterized by renal resistance to the antidiuretic hormone arginine vasopressin (AVP), which leads to polyuria, plasma hyperosmolarity, polydipsia, and impaired quality of living. Inherited forms are caused by X-linked loss-of-function mutations in the gene encoding the vasopressin 2 receptor (V2R) or autosomal recessive/dominant mutations in the gene encoding aquaporin 2 (AQP2). A common acquired form is lithium-induced NDI. AVP facilitates reabsorption of water through increased abundance and insertion of AQP2 in the apical membrane of principal cells in the collecting ducts. In X-linked NDI, V2R is dysfunctional, which leads to impaired water reabsorption. These patients have functional AQP2, and thus the challenge is to achieve AQP2 membrane insertion independently of V2R. The current treatment is symptomatic and is based on distally acting diuretics (thiazide or amiloride) and cyclooxygenase inhibitors (indomethacin). This mini-review covers published data from trials in preclinical in vivo models and a few human intervention studies to improve NDI by more causal approaches. Promising effects on NDI in preclinical studies have been demonstrated by the use of pharmacological approaches with secretin, Wnt5a, protein kinase A agonist, fluconazole, prostaglandin E2 EP2 and EP4 agonists, statins, metformin, and soluble prorenin receptor agonists. In patients, only casuistic reports have evaluated the effect of statins, phosphodiesterase inhibitors (rolipram and sildenafil), and the guanylate cyclase stimulator riociguat without amelioration of symptoms. It is concluded that there is currently no established intervention that causally improves symptoms or quality of life in patients with NDI. There is a need to collaborate to improve study quality and conduct formal trials.
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PMID:A mini-review of pharmacological strategies used to ameliorate polyuria associated with X-linked nephrogenic diabetes insipidus. 3292 47