Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adrenomedullin-2 (ADM2), a novel calcitonin/calcitonin-gene-related peptide family peptide, is reported to reduce blood pressure in both normal and hypertensive rats. This study demonstrates gestational regulation of circulatory ADM2 in rat plasma. ADM2 dose-dependently reduces the mean arterial pressure in rats, whereas the hypotensive effect of ADM2 is significantly higher during pregnancy. In addition, immunoreactive ADM2 protein is distributed in perivascular fibers of rat mesenteric artery, and levels of pre-pro-ADM2 are significantly (P<0.05) elevated in pregnant compared with nonpregnant rat mesenteric artery. Furthermore, incubation of endothelium intact arterial tissue from pregnant rats with ADM217-47, an ADM2 antagonist, shifted the dose-dependent relaxation curve to the right in wire myography. Inhibition of soluble guanylate cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 microM) or endothelial nitric oxide synthase with N-nitro-L-arginine methyl ester (100 microM) reduced the relaxation of mesenteric artery induced by ADM2. Inhibition of adenylate cyclase with SQ22536 (10 microM) or protein kinase A with the Rp diastereomer of cyclic adenosine 3',5'-phosphorothioate (10 microM) also reduced the maximal relaxation responses induced by ADM2. Blockade of calcium-activated potassium channels with tetraethylammonium chloride (1 mM) inhibited the ADM2-induced relaxation, whereas blockade of ATP-sensitive potassium channels with glybenclamide (10 microM) did not affect the relaxation response. Hence the mechanism of ADM2-induced vasorelaxation is nitric oxide and receptor mediated and cGMP and cAMP dependent and occurs through activation of calcium-activated potassium channels. In conclusion, rat pregnancy is associated with increased levels of circulatory and vascular tissue ADM2 with concomitant increase in the in vivo hypotensive effect of ADM2 and vascular reactivity of mesenteric artery to ADM2, thus suggesting involvement of ADM2 in vascular adaptations during pregnancy.
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PMID:Adrenomedullin-2, a novel calcitonin/calcitonin-gene-related peptide family peptide, relaxes rat mesenteric artery: influence of pregnancy. 1721 18

Calcitonin gene-related peptide (CGRP) is a highly potent vasodilator known to be involved in many physiological functions within the cardiovascular, gastrointestinal, immune, and nervous systems. This study assessed the desensitization of CGRP receptors by measuring agonist-mediated activation of adenylate cyclase in a model system employing human neuroblastoma-derived SK-N-MC cells. In these cells, we demonstrated that pre-incubation with CGRP (20 nM) induces a rapid desensitization of CGRP signaling (t(1/2)<or=3 min) by causing a decrease in potency and efficacy. CGRP's desensitization potency (DC(50)=0.29 nM) is similar to its activation potency on non-desensitized cells (EC(50)=0.20 nM). The desensitized receptors exhibited slow and incomplete re-sensitization upon removal of the pre-incubated ligand, resulting in 52-65% functional recovery after 3-5 h while CGRP binding sites were completely restored. Additional agonists within the calcitonin/CGRP family of peptides (calcitonin, amylin, adrenomedullin, and adrenomedullin 2) were compared to CGRP with regard to their ability to activate and desensitize CGRP receptors. Calcitonin and amylin did not cause receptor activation nor did they produce desensitization. Adrenomedullin and adrenomedullin 2 activated the receptors and produced desensitization, but at a slower rate and with a weaker desensitization potency than CGRP-induced desensitization. Adrenomedullin exhibited similar potency for receptor activation and desensitization, whereas adrenomedullin 2 has a 4-fold higher preference for receptor desensitization than for receptor activation. Activation and desensitization induced by CGRP, adrenomedullin and adrenomedullin 2 were blocked by the CGRP receptor antagonist CGRP8-37. These data indicate that CGRP receptors are desensitized by select peptides in the calcitonin/CGRP family. Slow recovery from the desensitized state may provide a strategy for timed modulation of the CGRP signaling pathway.
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PMID:Desensitization and re-sensitization of CGRP receptor function in human neuroblastoma SK-N-MC cells. 1782 80

The calcitonin gene-related peptide (CGRP) is a neuropeptide involved in vasodilation and other physiological functions throughout the body. The receptor for CGRP has been cloned and well studied, but the mechanism of CGRP receptor desensitization has not been fully elucidated. In the present study, we evaluated the kinetics for agonist-mediated desensitization of the adenylate cyclase response in human neuroblastoma SK-N-MC cells. Distinct CGRP receptor agonists were used, including alpha and beta isoforms of CGRP, the linearized derivative cys(Et)2,7 alphaCGRP, adrenomedullin, and adrenomedullin 2. betaCGRP was 4-600 times more potent at desensitizing the cAMP production as compared to the other receptor-activating ligands, and all of the desensitization effects were blocked by a CGRP receptor antagonist. Although the different agonists vary in their ability to induce functional desensitization, a pretreatment/washout sequence with each peptide was able to reduce the activation potency of the other members of the calcitonin/CGRP peptide family. Next we tested whether the desensitizing effects of the distinct peptides involve protein kinase C (PKC) or protein kinase A (PKA). A PKC inhibitor, Ro 31-8220, concentration-dependently reduced the desensitization induced by the 5 CGRP receptor agonists, while having little effect on their desensitization potencies. PKA inhibitors KT-5720 and H-89, on the other hand, showed little effect on the induced level of desensitization. The findings indicate that functional desensitization is produced by distinct peptides acting through the active site of CGRP receptors, and involves the activation of PKC as a common component necessary to achieve maximal desensitization of receptor signaling.
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PMID:Protein kinase C is a common component of CGRP receptor desensitization induced by distinct agonists. 1842 Jan 88

Calcitonin receptor-stimulating peptide (CRSP) and intermedin (IMD) are two recently discovered peptides in the calcitonin (CT) family of peptides. CRSP and IMD, similar to CT, calcitonin gene-related peptide (CGRP), and amylin (AMY), but in contrast to adrenomedullin (ADM), inhibited bone resorption in mouse calvarial bones. CRSP and IMD, similar to CT, CGRP, AMY, but in contrast to ADM, decreased formation of osteoclasts and number of pits in bone marrow macrophage cultures stimulated by M-CSF and RANKL, with no effect on the expression of a number of genes associated with osteoclast progenitor cell differentiation. CRSP and IMD inhibited osteoclastogenesis at a late stage but had no effect on DC-STAMP mRNA. IMD, similar to CGRP, AMY, and ADM stimulated cyclic AMP formation in M-CSF expanded osteoclast progenitor cells lacking CT receptors (CTRs). RANKL induced CTRs and a cyclic AMP response also to CT and CRSP, and increased the cyclic AMP response to CGRP, AMY, and IMD but decreased the response to ADM. Our data demonstrates that CRSP and IMD share several functional properties of peptides in the CT family of peptides, including inhibition of bone resorption and osteoclast formation. The data also show that the reason why ADM does not inhibit osteoclast activity or formation is related to the fact that RANKL decreases ADM receptor signaling through the adenylate cyclase-cyclic AMP pathway. Finally, the findings indicate that activation by CGRP, AMY, and IMD may include activation of both CT and CT receptor-like receptors.
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PMID:Comparisons between the effects of calcitonin receptor-stimulating peptide and intermedin and other peptides in the calcitonin family on bone resorption and osteoclastogenesis. 2174 86