Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adenylate cyclase responses of the human GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors to TRH, LH-RH, biogenic amines, peptides hormones, PGE1 and rat median eminence extract (MEE) have been examined. Out of 4 GH producing pituitary adenomas obtained from patients with active acromegaly at hypophysectomy two were stimulated by TRH, two by LH-RH, three by norepinephrine, one by dopamine, four by PGE1 and none by serotonin. Glucagon stimulated the adenylate cyclase in one of three and MEE in both of two tested. The positive responses of paradoxical GH release after TRH and/or LH-RH before surgery in these patients coincidentally related to the response of adenylate cyclase of each pituitary adenoma. There seems, however, to be no consistent correlation between the adenylate cyclase responses to biogenic amines and the GH release after L-Dopa or 5-hydroxytroptophan tested. The adenylate cyclase of a pituitary adenoma from case of Cushing's disease was stimulated by LH-RH, norepinephrine glucagon and MEE but not by TRH. Plasma levels of ACTH, beta-MSH and cortisol increased after LH-RH but not after TRH in this patient before hypophysectomy. The adenylate cyclase of two ectopic ACTH producing tumors (gastric carcinoid and malignant thymoma) was activated by TRH, LH-RH, norepinephrine, epinephrine, serotonin, PGE1 and MEE. These results indicate the presence of multiple hormone receptors in GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors, and suggest that the paradoxical GH or ACTH release after TRH and/or LH-RH injection in acromegaly and Cushing's syndrome might be caused by an alteration of the cellular membrane receptors of the pituitary adenomas.
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PMID:Adenylate cyclase of GH and ACTH producing tumors of human: activation by non-specific hormones and other bioactive substances. 19 Feb 56

The development of a long-acting somatostatin (SRIH) analog (octreotide, Sandoz) has been a major breakthrough in the treatment of acromegaly. However, in 20-30% of the patients, growth hormone (GH) plasma levels remain elevated (> 10 micrograms/l) despite treatment with octreotide. This raised the concept of resistance to SRIH analog therapy in acromegaly. Indeed, in vivo response to SRIH analogs varies greatly among acromegalic patients. According to the reviews in the literature and our own autoradiographic data, no direct correlation can be established between the GH response to octreotide and the number or affinity of the SRIH receptors located on the tumor. In our series a greater density of SRIH receptors is present on tumors from patients very sensitive to the SRIH agonist. A subset of patients resistant to octreotide could result from a very low density of SRIH receptor although this type of GH-secreting tumor constitutes certainly a rare case. A subset of GH-secreting pituitary tumors can be characterized by a mutation on the alpha subunit of the guanine nucleotide-dependent protein coupled to the stimulation of adenylate cyclase (G alpha s). This mutation results in a high basal adenylate cyclase activity and a low GHRH-stimulated activity. However, when the adenomas are separated according to their basal adenylate cyclase activity, SRIH is able to decrease cAMP levels in both types of tumor. In addition, in our series no direct correlation is observed between the SRIH inhibition of adenylate cyclase and the amount of SRIH-binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Resistance to somatostatin (SRIH) analog therapy in acromegaly. Re-evaluation of the correlation between the SRIH receptor status of the pituitary tumor and the in vivo inhibition of GH secretion in response to SRIH analog. 130 25

A 40-yr-old man who had acromegaly and hyperthyroidism due to a GH/TSH-secreting pituitary adenoma is described. Serum free T4 was 2.8 ng/dl, free T3 was 1.1 ng/dl, and TSH was 1.2-1.5 microU/ml; the latter was measured in an immunoradiometric assay with a sensitivity of 0.07 microU/ml. Serum TSH was immunologically identical to standard TSH and did not decrease during a T3 suppression test. Serum free alpha-subunit and the molar alpha-subunit to TSH ratio were high (6.1 ng/ml and 31.2, respectively). TRH administration induced significant increases in both GH (+129%) and alpha-subunit (+156%) levels. Conversely, dopamine infusion resulted in a decrease in serum GH (-66%) and alpha-subunit (-43%) levels, and subsequent administration of the dopamine antagonist sulpiride induced significant increases in both GH and alpha-subunit (+393% and +106%, respectively). Similarly, somatostatin infusion inhibited GH (-43%) and alpha-subunit (-61%) secretion. Serum TSH levels were not affected by TRH, dopamine, or somatostatin. The biological to immunological activity ratio of serum TSH purified by immunoaffinity chromatography and measured in an adenylate cyclase assay was significantly increased compared to that in serum from hypothyroid or euthyroid subjects [biological to immunological activity ratio, 6.9 +/- 0.2 (+/- SD) vs. 4.4 +/- 1.1; P less than 0.001]. In gel chromatography, the apparent mol wt of the patient's TSH was smaller than that of the controls. After adenomectomy, all of the altered parameters of pituitary function became normal. Double gold particle immunostaining of the adenomatous tissue showed that all of the cells contained secretory granules positive for GH and alpha-subunit, while very few cells were positive for TSH beta as well as GH and alpha-subunit. These data indicate that in this patient serum TSH had an apparent mol wt smaller than that of normal TSH and an increased biological activity which, along with the autonomous TSH secretion, account for hyperthyroidism in the presence of low normal TSH levels; alpha-subunit originated from the same adenomatous cells that secreted GH but not TSH, thus explaining the in vivo observation that alpha-subunit responses to several agents were dissociated from TSH responses and parallel to GH responses; and TSH and GH were colocalized in a minority of the neoplastic cells.
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PMID:Endocrine, biochemical, and morphological studies of a pituitary adenoma secreting growth hormone, thyrotropin (TSH), and alpha-subunit: evidence for secretion of TSH with increased bioactivity. 241 56

The correlation between response of plasma GH to GHRH and the GHRH-induced stimulation of the intracellular adenylate cyclase (AC) activity in pituitary adenoma cell membranes in acromegalic patients was investigated. Each peak plasma GH level after iv administration of GHRH ranged from 1.1 to 13.8 times the basal level in 13 acromegalic patients. On the other hand, the maximal stimulation of intracellular AC activity (cAMP production) induced by GHRH varied from 1.4 to 6.4 times the control level in each GH-producing pituitary adenoma cell membrane. A significant positive correlation (r = 0.89, P less than 0.005) between plasma GH response to GHRH and intracellular cAMP production stimulated by GHRH was observed in nine of the acromegalic patients. In contrast, the response of plasma GH to GHRH was significantly blunted, despite a fairly large production of intracellular cAMP stimulated by GHRH, in the other four acromegalic patients. These results suggest that GHRH-induced GH release from GH-producing pituitary adenomas of patients with acromegaly may be regulated not only by GHRH receptor-adenylate cyclase system but also modified by several other factors including somatostatin and Sm-C.
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PMID:Growth hormone releasing hormone-sensitive adenylate cyclase activity in growth hormone-producing pituitary adenoma: correlation to the response of plasma growth hormone to growth hormone releasing hormone in patients with acromegaly. 255 Feb 7

Somatostatin (SRIF) actions in the brain and pituitary are mediated by specific receptors. Using radioiodinated ligands it has been possible to characterize the kinetics of specific binding sites in the brain and pituitary, and to determine their cellular localization by autoradiography. At the pituitary level, the inhibition of growth hormone, prolactin and thyrotropin secretions induced by SRIF is mediated through a single binding site which is coupled to the inhibition of adenylate cyclase. In the brain, SRIF receptors are localized on neurons and glial cells and are also coupled to adenylate cyclase inhibition. Two sites are differentiated in the brain with an analogue of somatostatin, SMS 201995. In humans, SRIF-binding sites have been related to a number of pathologies. At the pituitary level, it has been shown that the number of binding sites was negatively correlated to growth hormone levels in acromegaly. Furthermore, SRIF-binding sites were undetectable in a patient which did not respond to SMS 201995 therapy. In the brain, meningiomas and gliomas are rich in SRIF binding sites. This suggests a possible role for SRIF on glia. In neurodegenerative diseases, cortical SRIF concentrations are decreased in Alzheimer's and Parkinson's disease associated with dementia while SRIF-binding sites are only affected in Alzheimer's disease. In conclusion, the physiological role of SRIF in the brain and pituitary can be evaluated by studying the receptors of the peptide. Such studies allow to question the implication of SRIF in endocrine and neuropathologies.
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PMID:Somatostatin receptors in brain and pituitary. 256 73

Octreotide is a long-acting somatostatin analog that inhibits cell growth and hormone secretion. It has been successfully used in the management of a variety of endocrine tumors (i.e., acromegaly, carcinoid tumors, gastrinomas). In vitro, octreotide suppresses adenylate cyclase activity, DNA synthesis, and cell growth in cultured thyroid cell lines. Previous studies examining the use of octreotide in the treatment of medullary thyroid cancers, in vivo, report symptomatic improvement from tumor-related hormonal hypersecretion; however, octreotide's ability to suppress tumor growth was limited. In the present study, we examine the efficacy of long-term octreotide administration in six subjects with metastatic thyroid carcinoma, including Hurthle cell (one subject), medullary (one subject) and papillary or mixed papillary/follicular cancer (four subjects). All of the subjects had documented recurrences of their thyroid tumors despite appropriate therapy, and were considered to be untreatable by conventional therapeutic modalities (i.e., radioiodine or surgery). Subjects were monitored while receiving relatively high doses (4 mg daily) octreotide subcutaneously for up to 12 months. Octreotide therapy was very well tolerated; mild gastrointestinal symptoms persisted throughout treatment in one subject. Octreotide did not significantly decrease tumor markers (e.g., thyroglobulin, calcitonin, carcinoembryonic antigen). The carcinomas progressed during treatment, as evidenced by an increase in the size and/or number of metastatic lesions. In summary, in this small series subcutaneous octreotide administration did not appear to be efficacious in the management of advanced thyroid cancers.
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PMID:Octreotide therapy in advanced thyroid cancer. 771 6

To determine the cellular mechanism(s) of the variability in GH responsiveness to octreotide in acromegaly, somatostatin (SRIH) receptor status was studied in 37 GH-secreting adenomas. SRIH receptor binding was always present in all GH-secreting adenomas either in membrane preparations (Exp A; n = 17) or by quantitative autoradiography (Exp B; n = 20). In membranes, maximal binding capacities ranged from 83-2331 fmol/mg protein; affinity was in the nanomolar range (Kd, 1.3 +/- 0.2 nmol/L). By quantitative autoradiography, SRIH-14 and octreotide were equally active in displacing [125I]SRIH binding in tumors (Spearman correlation rho = 0.92). IC50 values ranged from 3-22 nmol/L (mean +/- SE, 8.0 +/- 1.3 nmol/L). In Exp A, basal adenylate cyclase (AC) activity was high in 7 tumors (841 +/- 306 pmol/L cAMP x 30 min/mg protein) compared to that in the other 10 (252 +/- 92 pmol/L cAMP x 30 min/mg protein). In these 7 tumors, GH-releasing hormone (0.1 mumol/L) stimulation of AC was lower (53 +/- 11% vs. 297 +/- 48%), whereas SRIH (1 mumol/L) inhibition was higher (52 +/- 5% vs. 34 +/- 5%). Similar results were obtained with Exp B tumors. In both experiments, no correlation was apparent between SRIH-binding capacity and inhibition of AC. In Exp B, a variable decrease in mean plasma GH levels was observed (> or = 80% in 5 patients, between 50-80% in 8 patients, and < or = 50% in 5 patients) after a single sc injection of octreotide (100 micrograms). A modest correlation was found between the GH response to octreotide and SRIH-binding capacity (rho = 0.48) or SRIH inhibition of AC (rho = 0.61). The IC50 values to displace SRIH binding were lower in poorly responsive patients than in highly responsive ones (IC50, 4.6 +/- 1.9 and 13.9 +/- 2.7 nmol/L, respectively). These data indicate that an absence of SRIH receptors cannot account for the weak response to SRIH therapy in 20-30% of acromegalic patients. Alternatively, the weak correlation between either SRIH binding or SRIH inhibition of AC with octreotide inhibition of plasma GH levels might reflect the heterogeneity of SRIH receptor subtypes in GH-secreting adenomas.
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PMID:Somatostatin receptors, adenylate cyclase activity, and growth hormone (GH) response to octreotide in GH-secreting adenomas. 790 12

Mutations of Gs are found in 30 to 40% of the pituitary tumours responsible for acromegaly (somatotrope tumor), 10% of secreting thyroid tumors, and in the rare McCune-Albright syndrome. Gs is a member of the G protein family, which plays a major role in the mechanism of action of many hormones by coupling their membrane receptors to molecules called effectors, which general intracellular second messengers. Gs is responsible for the coupling of many receptors to adenylate cyclase which synthetizes cyclic AMP. The effect of the mutations of Gs is to permanently activate adenylate cyclase by a mechanism similar to the one exerted by cholera toxin. In the somatotrope cells adenylate cyclase is normally under the control of the hypothalamic hormone GH-RH, which stimulates both growth hormone secretion and cell proliferation. The mutations of Gs allow the somatotrope to escape from the control by GH-RH and to secrete and proliferate in an autonomous way, which leads to the development of a tumor responsible for acromegaly. The same mechanism explains the presence of Gs mutations in the other types of endocrine tumors. Therefore, the mutations transform the gene of Gs into an oncogene, gsp, which represents the first molecular explanation of an old concept familiar to endocrinologists: the autonomy of the secretion and proliferation of endocrine tumors.
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PMID:[G-proteins and endocrine tumors. The example of acromegaly]. 793 40

The functional study of SRIH receptors was performed in ectopic GHRH-secreting tumors from two patients with acromegaly; patient 1 presented with multiple endocrine neoplasia type 1 with GHRH- and insulin-secreting pancreatic tumors, and patient 2 presented with a multihormone-secreting carcinoid tumor (including GHRH and alpha-subunit secretion, as demonstrated by clinical and immunohistochemical studies). In both cases, plasma GH levels were responsive to octreotide. In patient 2, plasma GHRH and alpha-subunit levels were responsive to octreotide. In vitro perifusion studies of a tumor fragment from patient 1 also showed inhibition of GHRH secretion by SRIH. A high density of specific SRIH-binding sites was visualized by autoradiography in GHRH tumors from both patients. SRIH specific binding was much higher in the GHRH tumors (6.6-8.4 fmol/surface unit) than in the insulinoma (1.9 fmol/surface unit). The binding inhibition constant (IC50) was in the nanomolar range (0.9-3 nmol/L) in the GHRH tumors. SRIH-14 inhibited forskolin-stimulated adenylate cyclase in the GHRH tumors from both patients, but not in the insulinoma. The functional SRIH receptors negatively coupled to adenylate cyclase present in ectopic GHRH-secreting tumors mediate the inhibitory effect of octreotide on GHRH secretion and on previously underrecognized ectopic alpha-subunit secretion from carcinoid tumors.
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PMID:Presence of somatostatin receptors negatively coupled to adenylate cyclase in ectopic growth hormone-releasing hormone- and alpha-subunit-secreting tumors from acromegalic patients responsive to octreotide. 796 43

The application of DNA technology has led to significant progress in our understanding of the aetiology of GH-secreting pituitary tumours. X-chromosome inactivation and RFLP analysis has revealed that GH-secreting tumours are monoclonal in origin and thus arise as a consequence of a somatic mutation within a single cell. Using PCR and sequence analysis, such a mutation has been identified in 30-40% of tumours. This is the so-called gsp mutation in which the gene for the alpha s subunit of the Gs protein is converted to an oncogene the expression of which results in constitutive adenyl cyclase activity and thus excessive cAMP production. In our own studies, we demonstrate that it is unlikely that a defect within the promoter region of the GH gene will prove to be a cause of excessive GH secretion in acromegaly. In contrast, we have shown that the GH gene is hypomethylated in tumour derived DNA and this may account, at least in part, for abnormal GH gene expression.
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PMID:Recent advances in the molecular biology of growth-hormone secreting human pituitary tumours. 847 19


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