1.Uroguanylin inhibits H-ATPase activity and surface expression in renal distal tubules by a PKG-dependent pathway.
da Silva Lima V1, Crajoinas RO2, Carraro-Lacroix LR3, Godinho AN1, Dias JL1, Dariolli R2, Girardi AC2, Fonteles MC4, Malnic G3, Lessa LM5. Am J Physiol Cell Physiol. 2014 Sep 15;307(6):C532-41. doi: 10.1152/ajpcell.00392.2013. Epub 2014 Jul 16.
Cumulative evidence suggests that guanylin peptides play an important role on electrolyte homeostasis. We have previously reported that uroguanylin (UGN) inhibits bicarbonate reabsorption in a renal distal tubule. In the present study, we tested the hypothesis that the bicarbonaturic effect of UGN is at least in part attributable to inhibition of H(+)-ATPase-mediated hydrogen secretion in the distal nephron. By in vivo stationary microperfusion experiments, we were able to show that UGN inhibits H(+)-ATPase activity by a PKG-dependent pathway because KT5823 (PKG inhibitor) abolished the UGN effect on distal bicarbonate reabsorption and H89 (PKA inhibitor) was unable to prevent it. The in vivo results were confirmed by the in vitro experiments, where we used fluorescence microscopy to measure intracellular pH (pHi) recovery after an acid pulse with NH4Cl. By this technique, we observed that UGN and 8 bromoguanosine-cGMP (8Br-cGMP) inhibited H(+)-ATPase-dependent pHi recovery and that the UGN inhibitory effect was abolished in the presence of the PKG inhibitor.
2.Nicorandil stimulates a Na(+)/Ca(2+) exchanger by activating guanylate cyclase in guinea pig cardiac myocytes.
Wei J1, Watanabe Y2, Takeuchi K1, Yamashita K3, Tashiro M3, Kita S4, Iwamoto T4, Watanabe H1, Kimura J5. Pflugers Arch. 2016 Apr;468(4):693-703. doi: 10.1007/s00424-015-1763-8. Epub 2015 Dec 3.
Nicorandil, a hybrid of an ATP-sensitive K(+) (KATP) channel opener and a nitrate generator, is used clinically for the treatment of angina pectoris. This agent has been reported to exert antiarrhythmic actions by abolishing both triggered activity and spontaneous automaticity in an in vitro study. It is well known that delayed afterdepolarizations (DADs) are caused by the Na(+)/Ca(2+) exchange current (I NCX). In this study, we investigated the effect of nicorandil on the cardiac Na(+)/Ca(2+) exchanger (NCX1). We used the whole-cell patch clamp technique and the Fura-2/AM (Ca(2+) indicator) method to investigate the effect of nicorandil on I NCX in isolated guinea pig ventricular myocytes and CCL39 fibroblast cells transfected with dog heart NCX1. Nicorandil enhanced I NCX in a concentration-dependent manner. The EC50 (half-maximum concentration for enhancement of the drug) values were 15.0 and 8.7 μM for the outward and inward components of I NCX, respectively.
3.Resveratrol induces hepatic mitochondrial biogenesis through the sequential activation of nitric oxide and carbon monoxide production.
Kim SK1, Joe Y, Zheng M, Kim HJ, Yu JK, Cho GJ, Chang KC, Kim HK, Han J, Ryter SW, Chung HT. Antioxid Redox Signal. 2014 Jun 1;20(16):2589-605. doi: 10.1089/ars.2012.5138. Epub 2013 Nov 16.
AIMS: Nitric oxide (NO) can induce mitochondrial biogenesis in cultured cells, through increased guanosine 3',5'-monophosphate (cGMP), and activation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We sought to determine the role of NO, heme oxygenase-1 (HO-1), and its reaction product (carbon monoxide [CO]) in the induction of mitochondrial biogenesis by the natural antioxidant resveratrol.
4.Notch activation augments nitric oxide/soluble guanylyl cyclase signaling in immortalized ovarian surface epithelial cells and ovarian cancer cells.
El-Sehemy A1, Chang AC, Azad AK, Gupta N, Xu Z, Steed H, Karsan A, Fu Y. Cell Signal. 2013 Dec;25(12):2780-7. doi: 10.1016/j.cellsig.2013.09.008. Epub 2013 Sep 13.
Nitric oxide (NO) is generated by tumor, stromal and endothelial cells and plays a multifaceted role in tumor biology. Many physiological functions of NO are mediated by soluble guanylyl cyclase (sGC) and NO/sGC signaling has been shown to promote proliferation and survival of ovarian cancer cells. However, how NO/sGC signaling is modulated in ovarian cancer cells has not been studied. The evolutionarily conserved Notch signaling pathway plays an oncogenic role in ovarian cancer. Here, we report that all three ovarian cancer cell lines we examined express a higher level of GUCY1B3 (the β subunit of sGC) compared to non-cancerous immortalized ovarian surface epithelial (IOSE) cell lines. Interestingly, the highest expression of GUCY1B3 in ovarian cancer OVCAR3 cells is concurrent with the expression of Notch3. In IOSE cells, forced activation of Notch3 increases the expression of GUCY1B3, NO-induced cGMP production, and the expression of cGMP-dependent protein kinase (PKG), thereby enhancing NO- and cGMP-induced phosphorylation of vasodilator-stimulated phosphoprotein (VASP, a direct PKG substrate protein).