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

The effect of urocortin (Uro), a recently discovered neuropeptide with selectivity towards corticotropin-releasing hormone type 2 receptor, was tested on whole cell currents expressed by guinea-pig gastric antrum smooth muscle cells. Uro (1 pmol/l-1 nmol/l) caused a concentration-dependent increase of Ca2+-sensitive K currents (I(K)) up to 500% as compared to control currents and did not affect the kinetics and voltage-dependence of inward Ca2+ currents. The I(K)-increasing effect of Uro was fully antagonized by preliminary emptying of intracellular Ca2+ stores with ryanodine and cyclopiazonic acid, as well as by bath application of selective blockers of adenylyl cyclase and cAMP-dependent protein kinase (PKA), but not by inhibitors of guanylyl cyclase, cGMP-dependent protein kinase, and protein kinase C. Comparable I(K) increase was obtained by forskolin (activator of adenylyl cyclase), Sp-cAMPS (activator of PKA), or by intracellular application of the catalytic subunit of PKA. It was concluded that Uro binds to a selective receptor in antral smooth muscle cells where it stimulates I(K) via PKA-dependent increase of Ca2+ concentration near the plasma membrane due to enhanced release from intracellular calcium stores.
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PMID:Urocortin hyperpolarizes stomach smooth muscle via activation of Ca2+-sensitive K+ currents. 1122 90

Considerable plasticity can occur within the amino acid sequence of amphiphilic peptide hormones. This is particularly evident within the corticotropin-releasing factor (CRF) family of peptides where, despite less than 15% sequence similarity among the four paralogous lineages, all are capable of acting as high affinity ligands to members of the CRF receptor family. This suggests that these peptides could undergo many mutational changes and remain as high affinity ligands to their receptors as long as the functional motifs do not change radically. Because paralogous peptide lineages are a product of genome duplications, additional genes encoding peptide-like sequences, which through mutation have lost their functional integrity, may exist. Function to these sequences may be restored if the appropriate motifs are reinserted into the primary structure. We screened rat genomic DNA with highly degenerate polymerase chain reaction (PCR) primers targeted to hybridize with the termini of CRF-related sequences. One set of sauvagine-based primers hybridized with a 120-bp sequence. The theoretical peptide sequence (SV4) showed similarity to the CRF family of peptides at the primary structure level. The encoded sequence was prepared by solid-phase synthesis and its activity assayed against mouse R1 and human R1/R2 receptors. SV4 did not bind to either mouse or human variants of the R1 receptor, but did bind to the R2 receptor with an affinity comparable to human CRF. SV4 exhibited a similar efficacy of cellular activation as CRF in trials quantifying the acidification rate of human R2alpha-transfected Chinese hamster ovary (CHO) cells, but not R1-transfected cells. SV4 utilizes adenylate cyclase as the principal secondary messenger of R2 signal transduction but, unlike urocortin or sauvagine, does not activate guanylate cyclase-, calcium- or mitogen-activated protein (MAP) kinase-mediated pathways. These data suggest that this artificial peptide may be useful to understand the cyclic adenosine monophosphate (cAMP)-dependent component of the CRF-R2 signal transduction cascade, and that additional sequences in the genome may be used to engineer bioactive peptides.
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PMID:An artificial peptide with corticotropin-releasing factor receptor-2 (CRF-R2) selective properties: the role of primary structure in the induction of signal transduction pathways. 1236 28

Urocortin, a member of corticotropin releasing factor (CRF) peptide family, has positive chronotropic and inotropic effects on heart and also shows a vasodilatory effect. However, the mechanism underlying its vasodilatory effect has yet to be elucidated. Endothelium-dependent relaxation of resistance arteries is mainly achieved by activation of K+ channels. Therefore, we investigated possible role of K+ channels and hyperpolarization for the vasodilatory effect of urocortin using the isolated perfused rat mesenteric arteries. Urocortin (0.2 nM) produced a slow-onset decrease in the perfusion pressure of the mesenteric vascular bed, which was elevated by an alpha1-adrenoceptor agonist, phenylephrine (2-4 microM). Urocortin also hyperpolarized the main mesenteric artery. Removal of endothelium with saponin treatment considerably inhibited the relaxation and hyperpolarization induced by urocortin. In contrast, the hyperpolarization was not significantly changed by cyclooxygenase inhibitor, indomethacin (1 microM) and/or nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine (100 microM). Urocortin-induced relaxation was not affected by the combination of a guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 microM), indomethacin and N(omega)-nitro-L-arginine. However, the relaxation and hyperpolarization were abolished by high extracellular potassium concentration (40 mM) or by a large conductance Ca(2+)-activated K+ channel blocker, charybdotoxin (1 nM). Glibenclamide (1 microM), an ATP-dependent K+ channel inhibitor, did not affect the relaxation and hyperpolarization. These results suggest that urocortin causes endothelium-dependent relaxation and hyperpolarization of rat mesenteric arteries, probably through the activation of charybdotoxin sensitive Ca2+-activated K+ channels. These findings also indicate an essential role of the endothelium for the urocortin-elicited vascular relaxation and hyperpolarization.
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PMID:Urocortin induces endothelium-dependent vasodilatation and hyperpolarization of rat mesenteric arteries by activating Ca2+-activated K+ channels. 1778 57