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)

We have cloned and sequenced a cDNA (RPR4) encoding a new member of the secretin/calcitonin/parathyroid hormone (PTH) receptor family. RPR4 was identified by PCR of rat pituitary cDNA, and a full-length clone was isolated from a rat olfactory bulb cDNA library. When RPR4 was functionally expressed in COS 7 cells, cyclic adenosine monophosphate (cAMP) production was stimulated by vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptides (PACAP-38 and PACAP-27) and helodermin, with equal potency. Peptide histidine isoleucine (PHI) and rat growth hormone releasing hormone (rGHRH) also stimulated cAMP production at lower potency. This suggests that RPR4 encodes a novel VIP receptor which we have designated the VIP2 receptor. In situ hybridisation showed that mRNA for this receptor was present mainly in the thalamus, hippocampus and in the suprachiasmatic nucleus.
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PMID:The VIP2 receptor: molecular characterisation of a cDNA encoding a novel receptor for vasoactive intestinal peptide. 822 21

We have recently cloned CTRs from cDNA libraries prepared from porcine renal and human ovarian cell lines. In situ hybridization and Northern analysis confirm the widespread distribution of CTR mRNA in numerous tissues. Hydropathy plots of the predicted amino acid sequence of the receptors demonstrate multiple hydrophobic regions that could generate 7 transmembrane spanning domains, similar to other G protein-coupled receptors. Searches of databanks for proteins with related amino acid sequences reveals that the CTRs are closely related to the receptors for parathyroid hormone/parathyroid hormone related peptide, secretin, vasoactive intestinal peptide, growth hormone releasing hormone, glucagon-like peptide-1 and glucagon. These receptors have no significant sequence homology to other G protein-coupled receptors, and therefore, appear to comprise a distinct receptor family. Expression of the hCTR or pCTR in COS cells results in expression of high affinity CTRs which are coupled to adenylate cyclase (AC). The hCTR, however, demonstrates higher affinity for human and salmon CT compared to the pCTR. Both CTRs demonstrate low affinity binding and AC activation in response to calcitonin gene related peptide, amylin or secretin, providing a possible explanation for the cross-reactivity among these peptides in vivo. Stable transfectants expressing the pCTR increase cAMP levels and increases in cytosolic free Ca2+ concentration consistent with dual coupling to AC and phospholipase C. Additional studies will help to establish the structural basis for this functional property as well as the evolutionary relationship of the members of this newly identified family of receptors.
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PMID:Characterization of the structural and functional properties of cloned calcitonin receptor cDNAs. 822 1

By screening a rat brain cDNA library using a cloned mu opioid receptor cDNA as probe, a clone was identified that is very similar to both the mu and delta opioid receptor sequences. Transient expression of this clone in COS-7 cells showed that it encodes a kappa opioid receptor, designated KOR-1, which is capable of high-affinity binding to kappa-selective ligands. Treatment of transfected cell membranes with bremazocine, a kappa-selective agonist, resulted in a 53% decrease in adenylate cyclase activity, indicating that this kappa opioid receptor displays inhibitory coupling to adenylate cyclase. Thus, one member from each of the three opioid receptor types, mu, kappa and delta, has been molecularly cloned. Analysis of sequence similarities among these opioid receptors, as well as between opioid receptors and other G-protein-coupled receptors, revealed regions of sequence conservation that may underlie the ligand-binding and functional specificities of opioid receptors.
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PMID:Molecular cloning of a rat kappa opioid receptor reveals sequence similarities to the mu and delta opioid receptors. 824 Feb 67

Insect diuretic hormones and their receptors regulate fluid and ion secretion and thus are attractive targets for the design of novel insect control agents. A complementary DNA clone encoding a corticotropin-releasing factor-related diuretic hormone receptor from the tobacco hornworm Manduca sexta was isolated by expression cloning in COS-7 cells. The receptor consists of 395 amino acids and contains seven putative transmembrane domains. The expressed receptor binds M. sexta diuretic hormone, as well as several related insect diuretic peptides with high affinity. Furthermore, each of these peptides stimulate adenylate cyclase in COS-7 cells transfected with the receptor. The M. sexta diuretic hormone receptor is homologous to the receptors for calcitonin, secretin, vasoactive intestinal peptide, parathyroid hormone, glucagon-like peptide 1, growth hormone-releasing hormone, pituitary adenylate cyclase-activating polypeptide, and glucagon. The M. sexta diuretic hormone receptor is the first nonmammalian member of this family to be identified.
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PMID:Expression cloning of an insect diuretic hormone receptor. A member of the calcitonin/secretin receptor family. 827 84

We have utilized the polymerase chain reaction technique to selectively amplify a G protein-coupled receptor cDNA from rat kidney proximal convoluted tubule mRNA, which exhibits high homology with previously cloned serotonin receptors. Sequencing of a full-length clone isolated from a rat hippocampal cDNA library revealed an open reading frame of 1,212 base pairs encoding a 404-residue protein with seven hydrophobic regions predicted to represent transmembrane-spanning domains. Within the transmembrane regions, this receptor was found to be 44-50% identical with various members of the 5-HT1, 5-HT5, and 5-HT6 subfamilies with lower (37-40%) homology to the 5-HT2-like receptors. Northern blots revealed a approximately 3.6-kilobase transcript localized in various brain regions with the following rank order of abundance: hypothalamus > hippocampus = mesencephalon > cerebral cortex = olfactory bulb > olfactory tubercle. Expression of this clone in COS-7 cells resulted in the appearance of high affinity, saturable binding of [3H]lysergic acid diethylamide ([3H]LSD; KD = 5 nM) and [3H]serotonin ([3H]5-HT; KD = 1 nM). Among endogenous biogenic amines, only 5-HT completely inhibited radioligand binding. The inhibition of radioligand binding by other serotonergic agents revealed a pharmacological profile that does not correlate with any previously described serotonin receptor subtype. In addition, this receptor exhibits high affinity for a number of tricyclic antipsychotic and antidepressant drugs including clozapine, loxapine, and amitriptyline. In HEK-293 cells stably transfected with this receptor, serotonin elicits a potent stimulation of adenylylcyclase activity. The distinct structural and pharmacological properties of this receptor suggests that it represents a completely novel serotonin receptor subtype, which we propose to designate 5-HT7. Based on its pharmacology and its localization to limbic and cortical regions of the brain, it is likely that this receptor may play a role in several neuropsychiatric disorders that involve serotonergic systems.
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PMID:Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype. 839 62

Pituitary adenylate cyclase-activating polypeptide (PA-CAP) is a polypeptide hormone related to vasoactive intestinal polypeptide (VIP). Rat PACAP receptor cDNA was isolated from a brain cDNA library by cross-hybridization with rat VIP receptor cDNA. The recombinant PACAP receptor expressed in COS cells bound PACAP with about 1000 times higher affinity than VIP, and PACAP stimulated adenylate cyclase through the cloned PACAP receptor. The rat PACAP receptor consists of 495 amino acids, contains seven transmembrane segments, and has a significant similarity with other Gs-coupled receptors, such as VIP, glucagon, and secretin receptors. PACAP receptor mRNA was abundantly expressed in the brain, but not in the peripheral tissues except for the adrenal gland. In situ hybridization revealed a high level of expression of PACAP receptor mRNA in the hippocampal dentate gyrus, olfactory bulb, and cerebellar cortex.
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PMID:Molecular cloning and tissue distribution of a receptor for pituitary adenylate cyclase-activating polypeptide. 839 23

Serotonin modulates a wide range of physiological functions by activating multiple receptors, which are coupled to various effector systems. Using a strategy based on amino acid sequence homology between 5-hydroxytryptamine (5-HT) receptors, we have isolated from a mouse brain library a cDNA encoding a new 5-HT receptor, 5-HTx, that activates adenylate cyclase. Amino acid sequence comparisons revealed that the 5-HTx receptor was a distant relative of previously cloned 5-HT receptors, with the highest percentage of homology (42%) being with the 5-HTdro1 receptor, a Drosophila 5-HT receptor positively coupled to adenylate cyclase. In COS-7 cells transiently expressing the 5-HTx receptor, 5-HT induced an increase in cAMP levels that was dose dependent and saturable (EC50 = 45 nM). Agonists displayed the following rank order of potencies: 5-carboxamidotryptamine > 5-methoxytryptamine > 5-HT > RU 24969 > 8-hydroxy-2-(di-n-propylamino)tetralin. The most efficient antagonists in inhibiting the stimulatory effect of 5-HT were methysergide, methiothepin, mesulergine, metergoline, clozapine, ergotamine, and (+)-butaclamol. Membranes of COS-7 cells expressing the 5-HTx receptor displayed a single saturable binding site for [3H]5-HT. The order of potencies of various drugs in displacing [3H]5-HT binding was similar to the order obtained in cAMP experiments. The pharmacological profile of this receptor does not correspond to the profile of any of the classic 5-HT receptor subtypes. Expression of 5-HTx mRNA was highest in brainstem and lower in forebrain, cerebellum, intestine, and heart. The 5-HTx receptor might therefore correspond to 5-HT1-like receptors that have been shown to induce relaxation in porcine vena cava and guinea pig ileum as well as tachycardia in cat heart. The high affinity of the 5-HTx receptor for neuroleptic agents such as (+)-butaclamol and clozapine suggests also that this receptor might play a role in certain neuropsychiatric disorders.
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PMID:Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase. 839 87

We have cloned a human receptor for parathyroid hormone from a kidney complementary DNA library. The deduced sequence of 593 amino acids shows high homology to the previously cloned receptors from opossum and rat. Expressed in COS-1 cells, the human receptor binds to parathyroid hormone-(1-38) with high affinity (pKD = 8.5) and is functionally coupled to adenylate cyclase (pEC50 = 9.4). At high concentrations of agonist, the receptor also activates phosphoinositide turnover.
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PMID:Cloning and functional expression of a human parathyroid hormone receptor. 839 94

A putative endogenous cannabinoid ligand, arachidonylethanolamide (termed "anandamide"), was isolated recently from porcine brain. Here we demonstrate that this compound is a specific cannabinoid agonist and exerts its action directly via the cannabinoid receptors. Anandamide specifically binds to membranes from cells transiently (COS) or stably (Chinese hamster ovary) transfected with an expression plasmid carrying the cannabinoid receptor DNA but not to membranes from control nontransfected cells. Moreover, anandamide inhibited the forskolin-stimulated adenylate cyclase in the transfected cells and in cells that naturally express cannabinoid receptors (N18TG2 neuroblastoma) but not in control nontransfected cells. As with exogenous cannabinoids, the inhibition by anandamide of the forskolin-stimulated adenylate cyclase was blocked by treatment with pertussis toxin. These data indicate that anandamide is an endogenous agonist that may serve as a genuine neurotransmitter for the cannabinoid receptor.
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PMID:Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. 851 84

The TSH receptor (TSHR) and the LH/CG receptor (LHR) are members of the family of G protein-coupled receptors. Recently, point mutations conferring constitutive activity to the TSHR and LHR have been observed as a cause of toxic adenoma and familial/sporadic male pseudo-precocious puberty, respectively. When evaluated by transfection in COS-7 cells the wild-type (wt) TSHR displays definite constitutive activity towards Gs-dependent adenylylcyclase stimulation, while available evidence shows that the LHR does not. In order to compare the constitutive activity of both receptors, we performed functional studies in COS-7 cells using different assay conditions. Human TSHR and LHR cDNAs subcloned in the expression vector pSVL were transiently expressed in COS-7 cells and cAMP production was determined following incubation in a medium containing physiological concentration of NaCl [isotonic (NaCl)] or in the same medium without NaCl [hypotonic (NaCl-)] or where NaCl was replaced by an isoosmolar concentration of sucrose [isotonic (sucrose)]. Cells transfected with the TSHR showed higher basal cAMP levels over cells transfected with pSVL in all conditions tested. The effect was stronger when cells were incubated in isotonic (sucrose) buffer. Cells expressing LHR exhibited a minimal increase of cAMP levels over cells transfected with pSVL in isotonic (NaCl) buffer; however, a marked increase in basal cAMP levels was observed when cells were assayed in hypotonic (NaCl-) or isotonic (sucrose) buffers. Varying the pH or incubation temperature was without effect on the results obtained with both receptors. Our data show that despite extensive sequence similarity, the LH and TSH receptors differ markedly in their basal activity. The differential sensitivity of both receptors to low NaCl concentrations, suggests that the unliganded TSH receptor is less constrained than its LH homolog and may be more susceptible to activation by a wide spectrum of mutations.
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PMID:Differential effects of NaCl concentration on the constitutive activity of the thyrotropin and the luteinizing hormone/chorionic gonadotropin receptors. 854 96


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