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 (AM), a potent vasodilatory peptide has beneficial effects in the kidney IN VIVO. The major aim of the present study was to determine the presence of AM receptor and the biological outcomes of AM on kidney interstitial fibroblasts in culture. Utilizing RT-PCR we found that NRK-49F cells express calcitonin receptor like receptor (CRLR) and receptor activity modifying protein 2 (RAMP2) but not RAMP3. Treatment of these cells with AM resulted in a concentration-dependent increase in cAMP activation. The activation of adenylate cyclase system was enhanced by over-expression of CRLR, RAMP2 and RAMP3. Furthermore, AM-stimulated adenylate cyclase activity was inhibited by AM-[22-52] the AM receptor antagonist. AM also caused a PKA-dependent increase in CRE-luciferase activity. To test the biological consequences of AM treatment and the signaling pathways mediating them, we examined the effect of AM on proliferation of NRK-49F cells and the desensitization of AM receptor. AM caused a significant decrease in proliferation that was AM-receptor mediated but was PKA independent. In addition, AM also caused desensitization of cAMP response within a few minutes of treatment. This effect of AM was also not mediated via cAMP pathway as forskolin failed to desensitize AM receptor, and a PKA-inhibitor did not inhibit the desensitization. Taken together these results demonstrate that NRK-49F cells express functional AM receptor that when activated by AM results in a significant reduction of cell proliferation. Although cAMP activation by AM, as in other systems, is also observed in NRK-49F cells, PKA-independent pathways lead to some of the biological responses observed in these cells.
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PMID:Regulation of adrenomedullin signaling in kidney interstitial fibroblasts. 1463 Nov 46

1. The mechanisms involved in the fine adjustment of iris sphincter muscle tone are largely unknown. The aim of the present study was to clarify the effects of adrenomedullin on the resting tension of the bovine isolated iris sphincter muscle. 2. The motor activity of the bovine isolated iris sphincter muscle was measured isometrically. The effects of adrenomedullin on resting tension were analysed in the presence of indomethacin. The presence of adrenomedullin mRNA in the preparation was determined by reverse transcription-polymerase chain reaction. Immunolabelling for adrenomedullin was also performed. 3. Adrenomedullin significantly decreased the resting tension of the muscle. The relaxant effect of adrenomedullin was significantly inhibited by adrenomedullin (22-52), a putative antagonist for the adrenomedullin receptor, or calcitonin gene-related peptide (CGRP) (8-37), a putative antagonist for the CGRP1 receptor. The relaxant effect was almost completely blocked by a combination of adrenomedullin (22-52) and CGRP (8-37). 4. The relaxant effect of adrenomedullin was also significantly diminished by 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthesis, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. 5. Reverse transcription-polymerase chain reaction analysis showed that adrenomedullin mRNA was expressed in the muscle strip. Immunopositive staining for adrenomedullin was detected in blood vessel cells and in the iris sphincter muscle cells. 6. These results suggest that adrenomedullin may be an autocrine and paracrine regulator of the resting tension of the iris sphincter muscle. Its biological effects may be due to the direct involvement of adrenomedullin receptors and also to the stimulation of CGRP1 receptors. The stimulation of these receptors by the peptide leads to the activation of adenylate cyclase and soluble guanylate cyclase and subsequent relaxation of the muscle strip.
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PMID:Relaxant effect of adrenomedullin on bovine isolated iris sphincter muscle under resting conditions. 1612 Jan 96

Adrenomedullin (ADM) acts as an autocrine or a paracrine factor in the regulation of cardiac function. The intracellular mechanisms involved in the direct effect of ADM on adult rat ventricular myocytes (ARVMs) are still to be elucidated. In ARVMs from normal rats, ADM produced an initial (< 30 min) increase in cell shortening and Ca2+ transients and a marked decrease in both on prolonged incubation (> 1 h). Both effects were sensitive to ADM antagonist ADM-(22-52). Treatment with SQ-22536, an inhibitor of adenylate cyclase, blocked the positive inotropic effect of ADM and potentiated its negative inotropic effect. The negative inotropic effect was sensitive to inhibition by pertussis toxin (PTX), an inhibitor of Gi proteins and KT-5720, an inhibitor of PKA. The observations suggest a switch from Gs-coupled to PTX-sensitive, PKA-dependent Gi coupling by ADM in ARVMs. The ADM-mediated Gi-signaling system involves cAMP-dependent pathways because SQ-22536 further increased the negative inotropic actions of ADM. Also, because ADM is overproduced by ARVMs in our rat model of septic shock, ARVMs from LPS-treated rats were subjected to treatment with ADM-(22-52) and PTX. The decrease in cell shortening and Ca2+ transients in LPS-treated ARVMs could be reversed back with ADM-(22-52) and PTX. This indicates that ADM plays a role in mediating the negative inotropic effect in LPS-treated ARVM through the activation of Gi signaling. This study delineates the intracellular pathways involved in ADM-mediated direct inotropic effects on ARVMs and also suggests a role of ADM in sepsis.
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PMID:Gs and Gi coupling of adrenomedullin in adult rat ventricular myocytes. 1632 20

The mechanisms of relaxation of adrenomedullin were investigated in isolated mesenteric artery from pregnant rats. Adrenomedullin (1 nM-0.3 microM) produced concentration-dependent relaxation of endothelium-denuded mesenteric artery rings precontracted with norepinephrine at a concentration required to produce 70% of maximal response (ED70). The concentration-response curve of adrenomedullin was shifted to the right by adrenomedullin receptor antagonist adrenomedullin(22-52) (10 microM) or calcitonin gene-related peptide(8-37) (1 microM). Inhibition of adenylate cyclase by 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536) (10 microM) or protein kinase A [Rp-cyclic adenosine monophosphorothioate (Rp-cAMP); 10 microM] reduced the adrenomedullin-induced relaxation to the same magnitude. Adrenomedullin increased the intracellular cAMP level from 0.38 +/- 0.07 to 2.00 +/- 0.47 pmol/mg tissues, which was completely inhibited by adrenomedullin(22-52) (100 microM). Extracellular high potassium (80 mM), which inactivates the potassium channels, reduced the adrenomedullin-induced relaxation. Blockade of ATP-sensitive, voltage-gated, or inward rectifier potassium channels did not affect the adrenomedullin-induced relaxation. Blockade of calcium-activated K+ channels (KCa) by tetraethylammonium (1 mM) or iberiotoxin (100 nM) inhibited the adrenomedullin-induced relaxation, whereas there was no additional inhibition by SQ22536 or Rp-cAMP when KCa channels were already inhibited. In conclusion, this study provides evidence that cAMP-dependent protein kinase A and KCa channels seem to mediate as the cellular pathways in the adrenomedullin-induced endothelium-independent relaxation of mesenteric artery from pregnant rats.
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PMID:Endothelium-independent relaxation by adrenomedullin in pregnant rat mesenteric artery: role of cAMP-dependent protein kinase A and calcium-activated potassium channels. 1655 34

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

Adrenomedullin (ADM) and nitric oxide (NO) have been implicated in the pathogenesis of certain psychiatric disorders such as schizophrenia and bipolar disorder. ADM induces vasorelaxation by activating adenylate cyclase and stimulating the release of NO. These two molecules are known to influence cerebral activity. In this study, we aimed to examine the serum levels of ADM and NO in patients with major depression (MD). We enrolled 50 patients with MD and 50 healthy control subjects. The diagnosis of MD was established on the basis of a structured clinical interview using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The severity of depressive symptoms was evaluated using Hamilton's 17-item Depression Rating Scale. The mean serum levels of ADM and NO in patients with MD were significantly higher than those in healthy subjects (p=0.001, for both). The severity of psychomotor retardation in patients with MD was significantly correlated with the ADM (r=0.37, p=0.007) and NO levels (r=0.29, p=0.038). The patients with obvious psychomotor retardation had significantly higher levels of ADM and NO than did the patients with no psychomotor retardation (p=0.025, p=0.030). A significantly positive correlation was found between ADM and NO levels in patients with MD (r=0.79, p=0.001). Serum levels of ADM and NO levels were not correlated with the severity or duration of depression or depressive symptoms (except psychomotor retardation). In conclusion, our study indicates that serum levels of ADM and NO are elevated in patients with MD and that increased serum levels of ADM and NO may be associated with psychomotor retardation. The ADM-NO system may serve as a new target in the treatment of patients with MD and psychomotor retardation.
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PMID:Possible role of adrenomedullin and nitric oxide in major depression. 2386 66


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