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)

Adenylate cyclase is a key enzyme that couples with both the stimulatory and inhibitory G proteins (Gs and Gi). The cyclase has been purified and shown to be a glycoprotein of molecular weight 115,000-180,000. Cloning of cDNAs for adenylate cyclase showed that the cyclase is a member of a large family consisting of a variety of subtypes of the enzyme. These subtypes show different responses to calmodulin and G protein beta gamma subunits, and their distributions in tissues and organs are also different. This suggests that each subtype is involved in a particular physiological function. The general structure of adenylate cyclase is composed of two cytoplasmic domains and two membrane-spanning domains, each of which contains 6 transmembrane spans (12 spans in a molecule). The amino acid sequence of each cytoplasmic domain, which is thought to contain a nucleotide (ATP) binding site, is well-conserved among the various subtypes. This review also focuses on the regulation of adenylate cyclase activity by G protein subunits, particularly on several models for adenylate cyclase inhibition by Gi. As one of these mechanisms, direct inhibition of adenylate cyclase by the beta gamma subunits recently demonstrated by us will be discussed.
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PMID:[Structure of adenylate cyclase and the coupling with the receptor-G protein system]. 838 53

Thyrotropin (TSH) receptor is a cell surface receptor that shares a high degree of homology with other glycoprotein hormone receptors including lutropin-choriogonadotropin (LH/CG) and follicle-stimulating hormone (FSH) receptors. Although the extracellular domain of TSH receptor is important for ligand binding, no direct information is available on whether extracellular domain alone is sufficient for high-affinity binding. Moreover, mutations made in the second cytoplasmic loop or the cytoplasmic tail of TSH receptor were reported to reduce significantly the affinity of TSH binding. In an attempt to determine whether TSH receptor extracellular domain is sufficient for high-affinity TSH binding or whether it requires transmembrane regions, we made a construct (TSHR-EX/CMV) that encodes for only the extracellular domain plus a foreign hydrophobic tail. The TSHR-EX/CMV was transfected and stably expressed in Chinese hamster ovary (CHO) cells. The truncated receptor was anchored to the cell surface through the hydrophobic tail at the carboxyl terminus. High-affinity TSH binding was observed comparable to that of the cells transfected with full-length TSH receptor. The CHO cells transfected with TSHR-EX/CMV did not respond to TSH stimulation of adenylate cyclase, whereas the cells transfected with the full-length TSH receptor cDNA did. The data presented here show that the extracellular domain of TSH receptor is sufficient to confer high-affinity TSH binding.
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PMID:High-affinity binding of thyrotropin to the extracellular domain of its receptor transfected in Chinese hamster ovary cells. 839 80

We studied the mechanism of anti-tumour action of sulphydryl glycoprotein (SAGP) purified from an extract of Streptococcus pyogenes in vitro. SAGP rapidly inhibited the incorporation of nucleic acid precursors into murine fibrosarcoma (Meth A) cells before it inhibited the cell growth. SAGP-induced cell growth inhibition was diminished by incubating the cells with pertussis toxin (IAP), whereas the SAGP activity was augmented by incubating the cells with cholera toxin (CTX). Meth A cells exposed to SAGP underwent an increase in labelling of the alpha-subunit of an inhibitory guanine nucleotide-binding (Gi) protein in a subsequent IAP-catalysed [32P]ADP ribosylation of the cell membrane fraction. Gi alpha labelling was not increased either in the membrane from the Meth A cells exposed to heat-inactivated SAGP or in the membrane from L929 cells exposed to SAGP, in which growth was also unaffected. By contrast, SAGP caused no alteration in labelling the alpha-subunit of stimulatory guanine nucleotide-binding (Gs) protein in a subsequent CTX-catalysed ADP ribosylation of membrane fractions of Meth A and L929 cells. The amount of intracellular cAMP was decreased slightly in Meth A cells incubated with SAGP. Although the precise roles of Gs protein and adenylate cyclase in the cell growth inhibition induced by SAGP are not clear, these findings suggested that the modulation of Gi protein is involved in such SAGP-induced cellular events as the inhibition of nucleic acid synthesis and cell growth inhibition.
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PMID:Streptococcal glycoprotein-induced tumour cell growth inhibition involves the modulation of a pertussis toxin-sensitive G protein. 861 26

hCG is a glycoprotein hormone composed of an alpha-subunit, common to all gonadotropins and to TSH, and a hormone-specific beta-subunit. The non-covalent association of the two subunits is an obligatory step for the formation of biologically active hormones. The correct assembly of the heterodimer is also important for efficient secretion of the hormone, receptor binding, and signal transduction. Herein, we have demonstrated that expression of the two subunits from independent promoters present in a single recombinant baculovirus resulted in subunit association and secretion of biologically active holoprotein by the insect cells. To determine whether the active conformation of heterodimer could be achieved when the two subunits were synthesized in tandem on a single polypeptide chain, two single chain or yoked hCG1, the C-terminus of the complete beta-subunit (145 amino acid residues) was conjoined to the N-terminus of the alpha-subunit. Yoked hCG2 was similar, except that it contained the N-terminal 123 amino acid residues of the beta-subunit. Both yoked hCG molecules bound LH/CG receptor with high affinity and stimulated adenylate cyclase and progesterone levels in transformed mouse Leydig (MA-10) cells. Therefore, the alpha- and beta-subunits are able to fold into a biologically active conformation when covalently linked. Interestingly, when compared with urinary hCG, the hormone expressed in baculovirus-infected insect cells binds to the LH/CG receptor with higher affinity, but exhibits diminished signaling, thus providing another example of a partial dissociation between receptor binding and activation.
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PMID:Functional expression of yoked human chorionic gonadotropin in baculovirus-infected insect cells. 861 8

Previous observations suggested a concomitant relationship between the release of the variant surface glycoprotein (VSG) and the activation of adenylate cyclase in the bloodstream form of the parasitic protozoan Trypanosoma brucei. In order to evaluate this hypothesis, adenylate cyclase activity was measured in live trypanosomes subjected to different treatments known to induce the shedding of the VSG coat, namely low pH and trypsin digestion. In both cases adenylate cyclase activation occurred in parallel with the release of the VSG. The latter was found to be mediated by the glycosylphosphatidylinositol-specific phospholipase C that cleaves the glycosylphosphatidylinositol anchor of the protein (VSG lipase). Furthermore, both adenylate cyclase and VSG release were activated by the incubation of trypanosomes with specific inhibitors of protein kinase C, suggesting a repressive role for protein kinase C on both VSG lipase and adenylate cyclase activities. Significantly, in mutant trypanosomes lacking VSG lipase, adenylate cyclase was activated under conditions where VSG release did not occur. Moreover,VSG release was also found to occur in the absence of activation of the cyclase, as observed in the presence of low concentration of the thiol modifying reagent p-chloromercuriphenylsulfonic acid. These observations provide the first demonstration that release of the VSG in response to cellular stress is mediated by the VSG lipase and that while both release of the VSG and activation of adenylate cyclase occur in response to the same stimuli they are not obligatorily coupled.
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PMID:Simultaneous but independent activation of adenylate cyclase and glycosylphosphatidylinositol-phospholipase C under stress conditions in Trypanosoma brucei. 863 99

The effects of the beta 2-adrenoceptor agonist formoterol (50 nM) on the angiotensin II (20 nM)-induced Ca2+ response and changes in the cell volume and microviscosity of the plasma membrane of vascular smooth muscle cells were studied. Applied as a model substance for the stimulation of the phosphoinositide-phospholipase C pathway, angiotensin II has been used to simulate the bronchospasm of smooth muscle in asthma. Our results demonstrated that angiotensin II-induced smooth muscle contraction primarily involves an InsP3-mediated release of Ca2+ from intracellular stores and, to a minor extent, an enhanced influx of Ca2+ through the plasma membrane. Both the Ca2+ response and the contractile reaction were strongly antagonized by pretreatment of the cells with 50 nM formoterol. The protective effect of formoterol on smooth muscle contractions is proposed to be mainly related to a direct stimulation of beta 2-adrenoceptor-coupled cAMP generation. Moreover, it is predicted that the interaction between the beta 2-adrenoceptor glycoprotein and adenylate cyclase will be enhanced following a formoterol-associated decrease in the microviscosity of the plasma membrane.
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PMID:Simultaneous measurement of Ca2+ transients and changes in the cell volume and microviscosity of the plasma membrane in smooth muscle cells. Evaluation of the effect of formoterol. 867 8

Four genes for adenylate cyclase have been characterized in Trypanosoma brucei. One of them, esag 4 (for expression site associated gene 4) is present in different VSG (variant surface glycoprotein) gene expression sites and, thus, is only expressed in the bloodstream form of the parasite. The others, termed gresag 4.1, 4.2 and 4.3 (for genes related to esag 4) are expressed in both bloodstream and procyclic forms. In addition, we cloned a esag 4-related gene from T. congolense. Here we characterize the genomic organization of gresag 4.1 and 4.3. While gresag 4.3 is unique, gresag 4.1 exists as a multigenic family of at least nine members located on a 3-Mb chromosome. Six of them are clustered in a region of 300 kb, three copies being tandemly linked. The determination of the nucleotide sequence of a conserved 1.6 kb PstI fragment demonstrated the presence of two separate subgroups in this family. This gene arrangement is present in different isolates of T.b. brucei/rhodesiense/gambiense. Several gresag 4.1 copies are transcribed in both bloodstream and procyclic forms.
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PMID:Families of adenylate cyclase genes in Trypanosoma brucei. 881 63

This short review summarizes recent data on corticosteroid-binding globulin (CBG), especially enlightening results on regulation factors of CBG gene expression during ontogenesis. The role of CBG as a specific steroid carrier, a structurally conserved glycoprotein of 50-60 kD in vertebrate species, is well documented, but this knowledge has often been limited to the young or adult life since CBG levels are low in the neonate. However, CBG and CBG mRNA have been recently detected, sometimes, in relatively high amounts, in various fetal tissues of mammals including liver, lung, pancreas, adrenal and kidney. CBG can thus participate in glucocorticoid-inducible events crucial for maturation. Moreover, its original molecular cloning, followed by its chromosomal localization, has shed a new light on the CBG role, as a member of the serine protease inhibitors and substrates (SERPINS) superfamily. This evidenced a special and unexpected way of steroid hormones delivery to their sites of action. Additionally, two classes of CBG receptors have been characterized, and an adenylate cyclase activity has been measured when the CBG-glucocorticoid complex binds to cell membranes.
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PMID:Regulation factors of corticosteroid-binding globulin: lesson from ontogenesis. 896 82

In domestic ruminants such as the sheep, birth is effected through sequential maturation of the foetal hypothalamic-pituitary-adrenal (HPA) axis, leading to the increased output of cortisol. Factors regulating foetal pituitary adrenocorticotrophin (ACTH) secretion have been delineated, and these include corticotrophin releasing hormone (CRH), arginine vasopressin, prostaglandin (PG) E2 and endogenous opioids. The pre-partum increase in foetal plasma ACTH is associated with a rise in pro-opiomelanocortin (POMC) mRNA in the foetal pars distalis, and with an altered pattern of POMC post-translational processing. Foetal adrenal activation results from an increase in ACTH receptors and enhanced coupling through the Gs protein to adenylate cyclase, and increased expression of key steroidogenic enzymes including P450c17. Cortisol modulates the mechanism by which ACTH activates foetal adrenal function, through specific glucocorticoid receptors (GR) in the foetal adrenal cortex. Although the numbers of GR change with gestation, the relative abundance of GR mRNA does not, pointing to post-translational regulatory mechanisms. Cortisol also stimulates an increase in the concentration of its own high affinity binding protein (corticosteroid binding globulin; CBG) in the foetal circulation, apparently by increasing CBG gene expression in the foetal liver, and by altering the extent of foetal CBG glycosylation in a manner that would be expected to decrease the metabolic clearance of this glycoprotein. Clear evidence for placental CRH and ACTH production is lacking in sheep, but PGE2, produced in increasing amounts by the placenta during late pregnancy, may augment the drive to HPA maturation. Aspects of the maturational pathway of cortisol biosynthesis have been described in other species, including the horse, and some comparison is made with the more detailed information currently available from species such as the sheep.
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PMID:Foetal endocrine maturation. 907 35

The albumen gland is a compound tubular exocrine gland found in the female reproductive tract of freshwater pulmonate snails such as Helisoma duryi. It secretes a perivitelline fluid, composed of protein and polysaccharide complexes, and coats each fertilized egg. A 288-kDa native glycoprotein, composed of several 66-kDa subunits, was identified in soluble extracts of albumen gland. Forskolin stimulates the release of secretory granules, containing both proteins and polysaccharides, from the cytoplasm of the glandular cells. An acid extract of the central nervous system or the adenosine-3', 5'-cyclic monophosphate (cAMP) analogue 8-bromo cAMP, stimulates protein secretion from the gland. Pretreatment of the albumen gland with cAMP antagonist (Rp isomer of cAMP) inhibits the stimulatory effect of a brain extract. Digestion of brain extract with proteolytic enzymes abolishes its activity, suggesting the factor from the brain is peptidergic. The neuroactive agents serotonin, Phe-Met-Arg-Phe-amide, Tyr-Gly-Gly-Phe-Met-Arg-Phe-amide, small cardioactive peptide B, and caudodorsal cell hormone were also tested for potential secretion-promoting ability. Brain extracts were partially purified with a Sep-Pak C18 reverse-phase cartridge and indicate the peptide is relatively hydrophobic. These results suggest that a brain peptide promotes the secretion of perivitelline fluid, and this is mediated by the adenylate cyclase/cAMP signal transduction pathway.
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PMID:Release of proteins and polysaccharides from the albumen gland of the freshwater snail Helisoma duryi: effect of cAMP and brain extracts. 963 57


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