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)

Results obtained with the use of nonpeptide angiotensin II receptor antagonists have suggested the presence of multiple subtypes of angiotensin II receptors in rat adrenal gland. However, the effects of nonpeptide antagonists on second messenger production by angiotensin II have not been investigated. In rat liver, angiotensin II can both activate phospholipase C, generating inositol polyphosphates and raising internal calcium, and inhibit adenylate cyclase. DuP 753 and PD123177, two nonpeptide angiotensin II antagonists, were used to characterize the receptor population in rat liver and to investigate the possibility that different angiotensin II receptor subtypes couple to different second messenger pathways. DuP 753 could completely antagonize the binding of angiotensin II in rat liver membranes, with a K1 of 9.3 x 10(-9) M. PD123177 had no effect on the binding of angiotensin II in rat liver at concentrations between 1 x 10(-9) M and 3 x 10(-5) M, in contrast to its ability to inhibit angiotensin II binding in rat adrenal. At a concentration of 10(-5) M, DuP 753 could inhibit increases in internal free calcium, could prevent production of inositol polyphosphates, and could attenuate inhibition of adenylate cyclase produced by angiotensin II. PD123177 at concentrations between 1 x 10(-9) M and 3 x 10(-5) M was ineffective in all of these assays. The results indicate that DuP 753 can displace the binding of angiotensin II at all receptor sites in rat liver and that this drug can attenuate both of the second messenger events produced by the angiotensin II receptor.
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PMID:DuP 753 can antagonize the effects of angiotensin II in rat liver. 201 58

Radioligand binding studies identified two classes of 125I-angiotensin II-binding sites in rat liver membranes. High affinity binding sites (Kd = 0.35 +/- 0.13 nM, N = 372 +/- 69 fmol/mg of protein) were inactivated by dithiothreitol (0.1-10 mM) without any apparent change in low affinity binding sites (Kd = 3.1 +/- 0.8 nM, N = 658 +/- 112 fmol/mg of protein). Dithiothreitol inactivation was readily reversible but could be made permanent by alkylation of membrane proteins with iodoacetamide. Angiotensin II stimulation of glycogen phosphorylase in isolated rat hepatocytes (maximal stimulation 780%, EC50 = 0.4 nM) was completely inhibited by 10 mM dithiothreitol, a concentration which also abolished high affinity site binding; phosphorylase stimulation by glucagon and norepinephrine under these conditions was unaltered. Angiotensin II inhibition of glucagon-stimulated adenylate cyclase activity in hepatocytes required higher angiotensin II concentrations (EC50 = 3 nM) than phosphorylase stimulation and was not affected by dithiothreitol. Fractional occupancy of high affinity binding sites by 125I-angiotensin II correlated closely with angiotensin II-mediated phosphorylase stimulation, whereas occupancy of low affinity sites paralleled inhibition of adenylate cyclase activity. These data indicate that the physiologic effects of angiotensin II in rat liver are mediated by two distinct receptors, apparently not interconvertible, and provide the first evidence for angiotensin II receptor subtypes with differing biochemical features and mechanisms of action.
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PMID:Characterization of angiotensin II receptor subtypes in rat liver. 633 67

The kidney is an important target organ for angiotensin II. The diverse biologic effects of angiotensin II in the kidney and periphery suggest that angiotensin II may be interacting with more than one receptor. Recently, the synthesis of highly selective nonpeptide angiotensin II receptor antagonists and the expression cloning of the angiotensin receptor have unequivocally demonstrated the existence of at least two angiotensin II receptor subtypes, designated AT1 and AT2. Autoradiography and ligand binding studies have shown that most tissues, including the kidney, have a mixture of both receptor subtypes. The AT1 receptor is coupled via G proteins to traditional signal transduction mechanisms such as stimulation of phospholipase C, Ca2+ mobilization, and inhibition of adenylate cyclase. The AT2 receptor does not appear to be coupled to G proteins, and the signal transduction pathway(s) associated with this receptor is not known but may involve cGMP. In the kidney, as in the periphery, all of the major physiologic actions of angiotensin II appear to be mediated by activation of the AT1 receptor. In this review, the general characteristics of the AT1 and AT2 receptors and their distribution and function in the kidney will be discussed.
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PMID:Angiotensin II receptor subtypes in the kidney. 831 80

A general model for membrane receptor action mechanisms indicates that information detected by receptors in the cell plasma membrane is transmitted to biological effectors, normally mediated by coupling elements. Seven-site transmembrane receptors coupled to G-proteins likely represent the most conserved and diversified category of membrane receptors. Information transfer from the extracellular medium to the cell involves three membrane proteins: a receptor, a G-protein (which binds and hydrolyzes GTP during its cycle), and an effector that regulates intracellular ion levels or second messengers. They detect various messages: light emissions, odorant molecules, peptide hormones, neurotransmitters and proteins. Structures of these membrane proteins include an extracellular N-terminal part, seven transmembrane alpha-helices and an intracellular C-terminal part. They are coupled to a G-protein which is stimulated upon ligand-induced receptor activation. This activated G-protein exchanges a GDP molecule for a GTP molecule which in turn acts on the effector. The effector is an enzyme (adenylate cyclase, phospholipase C, etc.) or an ionic channel (K+, Ca++ channels, etc.). Recognition of the message (which is specified by the membrane receptor), following amplification through activation of several catalytic cycles of G-proteins and the effector, thus leads to cellular events: modification of genetic transcription, cell growth, intercellular communication and modulation of the membrane potential. The present article briefly summarizes results on this topic with special stress on the angiotensin II receptor which is currently being investigated in our laboratory.
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PMID:[Cellular information and communication: receptors coupled to g-proteins]. 929 62