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)

Tanshinone IIA, one of the main active components from Chinese herb Danshen, is widely used to treat cardiovascular diseases including arrhythmia in Asian countries especially in China. However, the mechanisms underlying its anti-arrythmia effects are not clear. In this study we investigate the effects of tanshinone IIA on human KCNQ1/KCNE1 potassium channels (I(Ks)), human ether-a-go-go-related gene potassium channels (hERG), Kv1.5 potassium channels, inward rectifier potassium channels (I(K1)) expressed in HEK 293 cells using patch clamp technique. Tanshinone IIA potently and reversibly enhanced the amplitude of I(Ks) in a concentration dependent manner with an EC(50) of 64.5 microM, accelerated the activation rate of I(Ks) channels, decelerated their deactivation and shifted the voltage dependence of I(Ks) activation to negative direction. Isoproteronol, a stimulator of beta-adrenergic receptor, at 1 microM and sodium nitroprusside (SNP), a NO donor, at 1 mM, had no significant effects on the enhancement of I(Ks) by 30 microM tanshinone IIA. N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), a selective protein kinase A inhibitor, at 0.1 microM and 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), a selective nitric oxide-sensitive guanylyl cyclase inhibitor, at 10 microM, also had no significant effects on the enhancement of I(Ks) by 30 microM tanshinone IIA. Tanshinone IIA did not affect expressed hERG channels, Kv1.5 channels and I(K1) channels. These results indicate that tanshinone IIA directly and specifically activate human cardiac KCNQ1/KCNE1 potassium channels (I(Ks)) in HEK 293 cell through affecting the channels' kinetics.
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PMID:Tanshinone IIA: a new activator of human cardiac KCNQ1/KCNE1 (I(Ks)) potassium channels. 1857 50

Nitric oxide (NO) is a gaseous signal mediator showing numerous important biological effects. NO has been shown in many instances to exhibit its action via the protein S-nitrosylation mechanism, in which binding of NO to Cys residues regulate protein function independently of activation of soluble guanylate cyclase. The direct link between protein S-nitrosylation and functional modulation, however, has been demonstrated only in limited examples. Furthermore, although most proteins have more than one Cys residue, the mechanism by which a certain Cys becomes a specific target residue of S-nitrosylation is poorly understood. We have previously reported that NO regulates currents through the cardiac slowly activating delayed rectifier potassium channel (I(Ks)) irrespective of soluble guanylate cyclase activation. Here we demonstrate using a biotin-switch assay that NO induced S-nitrosylation of the alpha-subunit of the I(Ks) channel, KCNQ1, at Cys(445) in the C terminus. A redox motif flanking Cys(445) and the interaction of KCNQ1 with calmodulin are required for preferential S-nitrosylation of Cys(445). A patch clamp experiment shows that S-nitrosylation of Cys(445) modulates the KCNQ1/KCNE1 channel function. Our data provide a molecular basis of NO-mediated regulation of the I(Ks) channel. This novel regulatory mechanism of the I(Ks) channel may play a role in previously demonstrated NO-mediated phenomenon in cardiac electrophysiology, including shortening in action potential duration in response to intracellular Ca(2+) or sex hormones.
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PMID:Redox- and calmodulin-dependent S-nitrosylation of the KCNQ1 channel. 1912 72