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)

Familial male-limited precocious puberty (FMPP) is an autosomal dominant gonadotropin-independent disorder. Affected males generally develop signs of precocious puberty in early childhood. They typically show Leydig cell hyperplasia and increased testosterone production typical for their age, whereas circulating LH concentrations remain prepubertal. Several dominant point mutations of the LH receptor gene were identified in pedigrees with familial male-limited precocious puberty and were shown to cosegregate with the disease. Here we report a novel heterozygote point mutation in the LH receptor gene of a Brazilian boy with gonadotropin-independent precocious puberty. This mutation substitutes alanine 568 with valine at the carboxyterminus of the third cytosolic loop of the LH receptor. The unoccupied mutant receptors confer constitutive activation of adenyl cyclase activity when expressed in COS-7 cells, resulting in 4-fold higher cAMP concentrations over baseline compared with cells expressing an equivalent number of wild-type receptors. The affinity of the mutant receptors to 125I-labeled human LH was not altered compared with the wild type. Mutations of the homologue alanine residue in the alpha 1-adrenergic (in vitro), FSH (in vitro), and TSH (naturally occurring) receptors also result in constitutive adenyl cyclase activation, suggesting that this alanine residue is crucial for signal transduction and a potential site for upregulatory/oncogenic mutations in G-protein coupled receptors.
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PMID:A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty. 762 48

A novel myotropic heptapeptide was isolated from an extract of 54,000 heads of adult Leptinotarsa decemlineata by means of high performance liquid chromatography (HPLC), using the Locusta migratoria oviduct motility bioassay as monitoring system. The full primary structure was established as H-Ala-Tyr-Asn-Gly-Pro-Leu-Ala-NH2. This peptide, designated as Led-MNP-I, has a unique structure and does not belong to any known vertebrate or invertebrate peptide family. Two adjacent Led-MNP-I-immunoreactive perikarya were found in each optic lobe and in each half of all thoracic ganglia. Its absence from the pars intercerebralis and neurohemal organs suggests that Led-MNP-I is not a neurohormone but a neurotransmitter or neuromodulator. Treatment of isolated oviducts with varying concentrations of Led-MNP-I did not elicit significant changes in the level of cAMP concentration, suggesting that cAMP does not act as a second messenger for Led-MNP-I. Instead, Led-MNP-I induces an elevation of IP3. Treatment with Led-MNP-I did not stimulate cAMP production in the Colorado beetle brain, but this could be due to the very small number of receptive cells present. Both tissues contained a forskolin-sensitive adenylate cyclase enzyme.
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PMID:Identification, characterization, and immunological localization of a novel myotropic neuropeptide in the Colorado potato beetle, Leptinotarsa decemlineata. 765 86

A number of analogues of vasopressin, incorporating the substitution of D-3'-(pyridyl)-alanine in position 2, were synthesized and tested for antidiuretic (V2), vasoconstrictor (V1a) and ACTH secretory (V1b; pituitary) activities. One analogue, deamino-[D-3'-(pyridyl)-alanine2]arginine-vasopressin (abbreviated d[D-3Pal]VP) was a potent pituitary agonist, weaker antidiuretic agonist, and weak vasoconstrictor antagonist. Another analogue, [D-3'-(pyridyl)-alanine2]arginine-vasopressin, had very weak pituitary activity but no measurable antidiuretic or vasoconstrictor activity. Other D-3'-(pyridyl)-alanine-substituted analogues had only very weak activity in one or two of the bioassays. In further examination of the relationship between the actions of vasopressin on generation of cyclic AMP and secretion of ACTH in pituitary cells, the cyclic AMP responses to d[D-3Pal]VP, to another analogue of vasopressin ([Val4,D-Arg8]VP) with potent agonist activity at pituitary and renal (V2) receptors, and to CRF were compared to that of vasopressin. At the prescribed concentrations, the ACTH secretory responses to vasopressin, d[D-3Pal]VP, and [Val4,D-Arg8]VP were comparable; but only ([Val4,D-Arg8]VP) and CRF, which did not change ACTH secretion, increased intracellular cyclic AMP. These results indicate the possibility of synthesizing analogues of vasopressin with selective activity for the pituitary response and the potential for further study of vasopressin receptor subtypes, using the D-3'-(pyridyl)-alanine substitution. They are also consistent with the concept that the ACTH secretory response to vasopressin by itself is not linked to cyclic AMP, although adenylate cyclase may be activated.
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PMID:Structure--function studies of vasopressin analogues with D-3 pyridyl-alanine in position 2. 765 89

The A2a adenosine receptor is a member of the G-protein coupled receptor family, and its activation stimulates cyclic AMP production. To determine the residues which are involved in ligand binding, several residues in transmembrane domains 5-7 were individually replaced with alanine and other amino acids. The binding properties of the resultant mutant receptors were determined in transfected COS-7 cells. To study the expression levels in COS-7 cells, mutant receptors were tagged at their amino terminus with a hemagglutinin epitope, which allowed their immunological detection in the plasma membrane by the monoclonal antibody 12CA5. The functional properties of mutant receptors were determined by measuring stimulation of adenylate cyclase. Specific binding of [3H]CGS 21680 (15 nM) and [3H]XAC (4 nM), an A2a agonist and antagonist, respectively, was absent in the following Ala mutants: F182A, H250A, N253A, I274A, H278A, and S281A, although they were well expressed in the plasma membrane. The hydroxy group of Ser-277 is required for high affinity binding of agonists, but not antagonists. An N181S mutant lost affinity for adenosine agonists substituted at N6 or C-2, but not at C-5'. The mutant receptors I274A, S277A, and H278A showed full stimulation of adenylate cyclase at high concentrations of CGS 21680. The functional agonist potencies at mutant receptors that lacked radioligand binding were > 30-fold less than those at the wild type receptor. His-250 appears to be a required component of a hydrophobic pocket, and H-bonding to this residue is not essential. On the other hand, replacement of His-278 with other aromatic residues was not tolerated in ligand binding. Thus, some of the residues targeted in this study may be involved in the direct interaction with ligands in the human A2a adenosine receptor. A molecular model based on the structure of rhodopsin, in which the 5'-NH in NECA is hydrogen bonded to Ser-277 and His-278, was developed in order to visualize the environment of the ligand binding site.
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PMID:Site-directed mutagenesis identifies residues involved in ligand recognition in the human A2a adenosine receptor. 777 60

Consequent to agonist exposure, many G protein-coupled receptors undergo sequestration or internalization. Results with receptors linked to adenylate cyclase, such as the beta 2-adrenergic receptor, or receptors linked to phospholipase C (PLC) have provided conflicting results regarding the role of second messenger-dependent (i.e., protein kinase A or C) and -independent (i.e., beta-adrenergic receptor kinase) kinases in mediating this process. Recent results for truncated and mutated gastrin-releasing peptide (GRP) receptors (GRP-R), as well as muscarinic cholinergic receptors, suggest that activation of protein kinase C may be needed for full receptor internalization. Nearly all G protein-coupled receptors studied to date, including the GRP-R, possess two highly conserved amino acids that are important in mediating receptor-G protein coupling to second messengers, i.e., arginine in the proximal second intracellular loop and alanine in the distal third intracellular loop. We selectively mutated each of these residues in the GRP-R to determine their importance for activation of PLC. Site-directed mutagenesis was performed to change arginine at position 139 to glycine (R139G mutant) and alanine at position 263 to glutamate (A263E mutant), with stable cell lines being created by transfection of the wild-type or mutated receptor cDNA into BALB/3T3 fibroblasts. Both R139G (Kd = 12.0 +/- 1.6 nM) and A263E (Kd = 12.2 +/- 1.7 nM) had a lower affinity for bombesin than did wild-type GRP-R (Kd = 1.4 +/- 0.4 nM); however, characteristic stoichiometries for the binding of agonists to this receptor were maintained equally in all three cell lines (bombesin > GRP >> neuromedin B). The wild-type GRP-R exposed to bombesin increased [3H]inositol phosphates (a measure of PLC activation) approximately 4-fold, with an EC50 of 5.1 +/- 2.2 nM. In contrast, [3H]inositol phosphates were not significantly increased in cells expressing R139G or A263E receptors, demonstrating that Arg139 and Ala263 are required for GRP-R activation of PLC. However, when receptor internalization at 37 degrees was assessed by ligand acid-stripping studies, 53 +/- 2% of A263E receptors were internalized at 90 min, compared with 85 +/- 5% of wild-type GRP-R, whereas only 10 +/- 3% of R139G receptors were internalized. Preincubation of either mutant cell line with 100 nM 12-O-tetradecanoylphorbol-13-acetate markedly increased internalization rates, such that at 90 min 62 +/- 2% of R139G receptors and 82 +/- 1% of A263E receptors were internalized.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Internalization of the gastrin-releasing peptide receptor is mediated by both phospholipase C-dependent and -independent processes. 793 30

Structure-activity relationships were determined for the natural bag cell peptides (BCPs) and for a series of synthetic analogues in terms of their ability to stimulate (at 30 degrees C) and to inhibit (at 15 degrees C) bag cell adenyl cyclase. We found that the core RLRF motif shared by all these peptides is active in this assay, and is stimulatory. The histidine residue C-terminal to this motif in beta-BCP is superfluous in this respect. An electronegative residue C-terminal to RLRF is sufficient to induce temperature-dependent function. The Ala-Pro pair that is N-terminal to this motif in alpha-BCP increases potency, but does not alter function.
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PMID:Determinants of potency and temperature-dependent function in the Aplysia bag cell peptides. 798 5

The mu opiate receptor is a principal brain site for activities of morphine, other opiate drugs, and opioid peptides in modulating pain and altering mood. Recent cloning of cDNAs encoding rat and human mu receptors reveals charged amino acid residues within putative transmembrane domains (TMs) II, III, and VI, a substantial N-terminal extracellular domain, and a C-terminal intracellular domain. Deletion of 64 N-terminal amino acids produced little effect on receptor function (Wang, J.B., Imai, Y., Eppler, C.M., Gregor, P., Spivak, C.E., and Uhl, G.R. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10230-10234). Further deletion of 33 C-terminal amino acids yielded a receptor at which morphine, but not the substituted enkephalin DAMGO ([D-Ala2,MePhe4,Glyol5]enkephalin), inhibited adenylate cyclase. Alanine substitution for each charged TM residue in the N-terminally deleted receptor reduced affinities for morphine, DAMGO, and the opiate antagonist naloxone. Replacement of TM II Asp114 with asparagine or glutamic acid increased mu receptor affinity for naloxone. TM II and TM III glutamic acid substitutions for Asp114 and Asp147 reduced agonist binding affinities but allowed full inhibition of adenylate cyclase at high agonist concentrations. TM VI histidine substitution with alanine yielded a receptor that produced almost twice the cyclase inhibition displayed by the wild type receptor in parallel transient expression assays. These findings underscore the importance of charged residues in TM II, III, and VI for different receptor functions and the modest involvement of extensive portions of N- and C-terminal receptor domains in these processes.
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PMID:-mu opiate receptor. Charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity. 805 Nov 54

The platelet-activating factor (PAF) receptor couples with multiple signaling pathways such as activation of phospholipase C, phospholipase A2, and mitogen-activated protein kinase and the inhibition of adenylate cyclase. The PAF-induced signals are attenuated by repetitive or long standing applications of the agonist (homologous desensitization). To investigate mechanisms underlying the agonist-induced desensitization, we constructed mutant forms of the cloned guinea pig PAF receptor and stably expressed them in Chinese hamster ovary cells. The cells expressing the wild type receptor transiently activated phospholipase C in response to PAF. Intracellular inositol 1,4,5-trisphosphate level and intracellular Ca2+ concentration reached the maximal levels within 20 s and returned to the basal levels in several minutes, even in the continuous presence of the ligand. In contrast, a truncated PAF receptor lacking the carboxyl-terminal cytoplasmic tail induced sustained elevations of inositol 1,4,5-trisphosphate and intracellular Ca2+ concentrations. Similar findings were noted in another mutant, in which the Ser/Thr residues in the carboxyl-terminal tail were substituted with Ala. Both mutant PAF receptors more potently activated the other signals (mitogen-activated protein kinase kinase, arachidonate release, and inhibition of adenylate cyclase) than did the wild type receptor. Thus, while the carboxyl-terminal cytoplasmic tail of the PAF receptor is not required for the forward activation of multiple signals, it does have a critical role for signal attenuation induced by the agonist through phosphate accepters. We also noted that the synthetic peptide of the PAF receptor carboxyl-terminal tail was strongly phosphorylated by the recombinant beta-adrenergic receptor kinase 1, suggesting that it or its relatives might be involved in PAF receptor phosphorylation and homologous desensitization.
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PMID:Role of cytoplasmic tail phosphorylation sites of platelet-activating factor receptor in agonist-induced desensitization. 807 75

Activation of cAMP-dependent protein kinase (cAPK) or protein kinase C (PKC) causes a rapid desensitization of beta 2-adrenergic receptor (beta AR) stimulation of adenylylcyclase in L cells, which previous studies suggest involves the cAPK/PKC consensus phosphorylation site in the third intracellular loop of the beta AR, RRSSK263. To determine the role of the individual serines in the cAPK- and PKC-mediated desensitizations, wild type (WT) and mutant beta ARs containing the substitutions, Ser261-->Ala, Ser262-->Ala, Ser262-->Asp, and Ser261/262-->Ala, were constructed and stably transfected into L cells. Results showed that serine 262 was the primary site of the cAPK-induced desensitization, whereas either serine 261 or serine 262 was sufficient to confer the 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA)/PKC-mediated desensitization. Coincident stimulation of cAPK and PKC caused an additive desensitization (6-8-fold increase in the EC50) which was significantly reduced (80%) only by the double substitution mutation. Quantitative evaluation of the coupling efficiencies and the GTP-shift of the WT and mutant receptors demonstrated that only one of the mutants, Ser262-->Ala, was partially uncoupled. The Ser262-->Asp mutation did not significantly uncouple, demonstrating that introducing a negative charge did not appear to mimic the desensitized state of the receptor. The beta AR expression level played a critical role in determining the pattern of beta AR desensitization; i.e. while the overall desensitization was unaltered within a large range of beta AR expression level (10-300 fmol/mg), the increase in EC50 and decrease in Vmax were differentially affected by the change in the receptor level.
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PMID:cAMP-dependent protein kinase and protein kinase C consensus site mutations of the beta-adrenergic receptor. Effect on desensitization and stimulation of adenylylcyclase. 808 4

The A1 adenosine receptor is a member of the seven-transmembrane G protein-coupled, receptor superfamily. This receptor binds the purine nucleoside adenosine with high affinity and inhibits the activity of adenylate cyclase. We have used site-directed mutagenesis and functional expression studies to examine the role of the threonine residue, located at position 277 in transmembrane domain VII of the human A1 receptor. Mutation of Thr-277 to either serine or alanine resulted in the expression of receptors that had essentially no change in binding affinity for the A1 selective antagonist 8-cyclo-pentyl-1,3-dipropylxanthine. Mutation of Thr-277 to serine resulted in modest (4.4-8.6-fold) but significant increases in the observed Ki values for three adenosine agonists, namely N-(1-methyl-2-phenethyl)adenosine (R-PIA or S-PIA) and 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-beta-L- ribofuranuronamide) (NECA). However, mutation of Thr-277 to alanine resulted in no significant changes in the Ki for R-PIA or S-PIA but did result in a highly significant 437-fold increase in the Ki for NECA. This demonstrates that the hydroxyl moiety of Thr-277 mediates agonist but not antagonist binding and, more specifically, that this residue forms a probable molecular contact site with the 5' substitution found in NECA.
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PMID:A threonine residue in the seventh transmembrane domain of the human A1 adenosine receptor mediates specific agonist binding. 830 May 61


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