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)

Cyclic GMP is central to visual excitation in vertebrate retinal rod cells. Sodium channels in the plasma membrane of the outer segment are kept open in the dark by a high level of cGMP. Light closes these channels by activating an enzymatic cascade that leads to the rapid hydrolysis of cGMP. Photoexcited rhodopsin triggers transducin by catalyzing the exchange of GTP for bound GDP. The activated GTP-form of transducin then switches on the phosphodiesterase by overcoming an inhibitory constraint. The overall gain of this cascade is about 10(5). The cascade is turned off by the GTPase activity of transducin and by the action of rhodopsin kinase and arrestin. One of the challenges now is to delineate the interplay of cGMP, calcium ion, and phosphoinositides in excitation and adaptation. Transducin belongs to a family of signal-coupling proteins that includes the G proteins of the hormone-regulated adenylate cyclase cascade. The initial events in visual excitation in molluscs and arthropods are probably similar to those of vertebrates. The triggering of transducin by photoexcited rhodopsin is a recurring motif in visual transduction. The coming together of electrophysiology, biochemistry, and molecular genetics affords new opportunities in unraveling the molecular mechanism of visual transduction.
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PMID:Cyclic GMP cascade of vision. 242 11

In the retinas of teleost fish dopamine, released from interplexiform cells, modulates synaptic transmission at both the chemical and electrical synapses of retinal horizontal cells. This modulation is due to activation of adenylate cyclase and phosphorylation by protein kinase A, perhaps of the synaptic ion channel proteins themselves. In this study we have fractionated the white perch retina by Percoll density gradient centrifugation in order to identify proteins which coenrich with horizontal cells. In addition we have tested retinal fractions for phosphorylation by native cAMP-dependent kinase. Our findings indicate that there are at least 3 proteins of molecular weights 28, 43/44 and 50 kDa which coenrich with horizontal cells and 3 proteins of 30/31 kDa, 35 kDa (putative rhodopsin) and 48 kDa (putative arrestin) which coenrich with photoreceptor fractions. The 43/44 kDa phosphoprotein is a target for cAMP-dependent protein phosphorylation and thus is apparently an element of the dopaminergic modulatory pathway in perch horizontal cells.
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PMID:Protein content and cAMP-dependent phosphorylation of fractionated white perch retina. 782 Jun 51

During myocardial ischemia, a local release of noradrenaline coincides with an increased density of beta-adrenergic receptors. The functional activity of these receptors, however, is mainly determined by their state of phosphorylation. The beta-adrenergic receptor kinase (beta ARK) specifically phosphorylates and thereby inactivates beta-adrenergic receptors after stimulation by receptor agonists, facilitating the binding of the inhibitor protein beta-arrestin to the receptors. beta ARK activation involves a translocation of the enzyme to the membrane. In the present study, we investigated the density and the functional activity of beta-adrenergic receptors, the enzymatic activity of beta ARK in membranes and cytosol, the mRNA levels of beta ARK-1, and the expression of beta-arrestin during stop-flow and low-flow ischemia in the isolated perfused rat heart. After 60 minutes of stop-flow ischemia, beta-adrenergic receptor density was upregulated, but beta-agonist-mediated adenylate cyclase activity was blunted. Simultaneously, beta ARK activity in the particulate fraction was significantly induced. The increase in beta ARK activity was reversible after inhibition of ischemia-evoked noradrenaline release by desipramine. Also, exposure to externally given noradrenaline increased beta ARK activity in the particulate fraction. Cytosolic beta ARK activity remained largely unchanged during stop-flow or low-flow ischemia. The steady state concentration of beta ARK-1 mRNA increased after 20 minutes of stop-flow ischemia and then returned to baseline values after another 20 minutes. Cardiac ischemia did not alter beta-arrestin levels. During myocardial ischemia, an increase in the number of beta-adrenergic receptors is paralleled by increased membrane activity of the receptor kinase beta ARK. This increased membrane activity may contribute to enhanced receptor phosphorylation and inactivation.
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PMID:Activation of beta-adrenergic receptor kinase during myocardial ischemia. 878 79

The human beta-adrenoceptor is a member of the seven-transmembrane family of receptors, encoded by a gene on chromosome 5. beta-Adrenoceptors have been classified into beta1, beta2, and beta3 subgroups, with beta2-receptors being widely distributed in the respiratory tract, particularly in airway smooth muscle. Intracellular signaling following beta2-adrenoceptor activation is largely affected through a trimeric Gs protein coupled to adenylate cyclase. Cyclic AMP (cAMP) induces airway relaxation through phosphorylation of muscle regulatory proteins and attenuation of cellular Ca2+ concentrations. Alternative cAMP-independent pathways involving activation of membrane maxi-K+ channels and coupling through Gi to the MAP kinase system have also been described. Site-directed mutagenesis has identified Asp 113 and Ser 204/207 within the third and fourth membrane domains as the active site of the beta2-receptor, critical for beta2-agonist binding and activity. beta2-Agonists have been characterized as those that directly activate the receptor (albuterol), those that are taken up into a membrane depot (formoterol), and those that interact with a receptor-specific auxiliary binding site (salmeterol). These differences in mechanism of action are reflected in the kinetics of airway smooth muscle relaxation and bronchodilation in patients with asthma. beta-Adrenoceptor desensitization associated with beta2-agonist activation is a consequence of phosphorylation by beta-ARK and uncoupling of the receptor from Gs following beta-arrestin binding, of internalization and recycling of the receptor through processes of sequestration and resensitization and downregulation, modulated by an effect on receptor gene expression. The degree of receptor desensitization appears to differ, depending on the cell or tissue type, and is reflected in the different profiles of clinical tolerance to chronic beta2-agonist therapy. A number of polymorphisms of the beta2-receptor have been described that appear to alter the behavior of the receptor following agonist exposure. These include Arg-Gly 16, Glu-Gln 27, and Thr-lle 164. The Gly 16 receptor downregulates to a greater extent and is associated with increased airway hyperreactivity, nocturnal symptoms, and more severe asthma. The Glu 27 form appears to protect against downregulation and is associated with less reactive airways. An individual can be homozygous or heterozygous for given polymorphisms, and large populations will have to be studied to determine their importance to the asthma phenotype.
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PMID:The beta-adrenoceptor. 981 38

Over the past 20 years, the general mechanism for signaling through 7-transmembrane helix receptors coupled to GTP hydrolysis has been worked out. Although similar in overall organization, subtype variability and subcellular localization of components have built in considerable signaling specificity. Atomic resolution structures for many of the components have delineated the domain organization of these complex proteins and have given physical form to the idea of subtype specificity. This review describes what is known about the physical structures of the 7-transmembrane helix receptors, the heterotrimeric GTP binding coupling proteins, the adenylate cyclase and phospholipase C effector proteins, and signaling modulatory proteins, such as arrestin, phosducin, recoverin-type myristoyl switch proteins, and the pleckstrin homology domain of G-protein receptor kinase-2. These images allow experimenters to contemplate the details of the supramolecular organization of the multiprotein complexes involved in the transmission of signals across the cellular lipid bilayer.
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PMID:Structural features of heterotrimeric G-protein-coupled receptors and their modulatory proteins. 1037 66

The physiological effects of the pituitary hormone, adrenocorticotropic hormone (ACTH) on the adrenal are mediated by the melanocortin 2 receptor (MC2R), a G protein coupled receptor (GPCR) that signals via adenylate cyclase to elevate intracellular cyclic AMP (cAMP) levels. The function and expression of the receptor is likely to be a major determinant of the response to ACTH. Following repeated stimulation, the cAMP signal is diminished or desensitized. Prolonged desensitization may involve internalization of the receptor. Internalization may occur by at least two mechanisms--receptor mediated endocytosis via clathrin-coated pits and by caveolae mediated internalization. The mode of internalization for the endogenous MC2R in Y1 cells was determined using radiolabelled ACTH. Treatment of Y1 cells with hypertonic sucrose or with concanavalin A, which inhibit clathrin-mediated endocytosis, blocked internalization. Filipin and nystatin, which inhibit caveolae formation, did not influence internalization. A dominant negative GRK2 inhibited internalization whilst the protein kinase A (PKA) consensus site mutant MC2R (S208A) internalized normally. However, dominant negative V53D beta-arrestin-1 did not inhibit ACTH internalization in Y1 cells. In conclusion, it appears that the MC2R in Y1 cells internalizes by a G protein coupled receptor kinase (GRK) dependent clathrin-coated pit mechanism.
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PMID:Agonist activated adrenocorticotropin receptor internalizes via a clathrin-mediated G protein receptor kinase dependent mechanism. 1253 Jun 27

We have previously shown that the human somatostatin receptor type 1 (hSSTR1) does not undergo agonist-induced internalization, but is instead up-regulated at the membrane upon prolonged somatostatin (SST) exposure. The deletion of the carboxyterminal C-tail of the receptor completely abolishes up-regulation. To identify molecular signals that mediate hSSTR1 up-regulation, we created mutant receptors with progressive C-tail deletions. Up-regulation was found to be absent in mutants lacking residues Lys359-Ser360-Arg361. Moreover, point mutation of Ser360 to Ala completely abolished up-regulation. The coexpression of wild type hSSTR1 with V53D, a dominant negative mutant of beta-arrestin-1, completely blocked hSSTR1 up-regulation. Further analysis demonstrated that calcium-calmodulin (CaM) dependent kinases were essential for the SST-induced up-regulation response. Like wild type receptors, all mutants failed to internalize after agonist exposure and were able to inhibit forskolin-stimulated cAMP accumulation. Taking these data together, we suggest that SST-induced hSSTR1 up-regulation is critically dependent upon a specific Lys-Ser-Arg sequence in the C-tail of the receptor, with Ser360 being essential. Up-regulation also requires the participation of CaM protein kinases and interactions with beta-arrestins. In contrast, coupling to adenyl cyclase (AC) and internalization occur independently of molecular signals in the receptor's C-tail.
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PMID:Agonist-induced up-regulation of human somatostatin receptor type 1 is regulated by beta-arrestin-1 and requires an essential serine residue in the receptor C-tail. 1589 21

Alpha2-adrenergic receptor agonists exert potent analgesic and sedative/hypnotic effects. In addition, they have been shown to be neuroprotective, but the mechanisms of these actions are still poorly defined. To isolate proteins that may control alpha2-adrenergic receptor function or trafficking, we performed a two-hybrid screen using the carboxy-terminal fourth intracellular tail of the alpha2A-adrenergic receptor as bait. This screen identified the amyloid precursor like protein 1 (APLP1), a homologue of the beta-amyloid precursor protein involved in Alzheimer's disease, as alpha2A-adrenergic receptor-binding protein. GST affinity chromatography revealed that APLP1 specifically interacts with all three human alpha2-adrenergic receptor subtypes and deletion mutant analysis confined the APLP1 domain involved in binding to alpha2-adrenergic receptors to the 13 amino acid residues Ser599-Ala611. Coimmunoprecipitations of transiently transfected cells with epitope-tagged APLP1 and alpha2-adrenergic receptors confirmed the interaction. Agonist treatment tended to increase the amount of alpha2A-adrenergic receptor associated with APLP1 while coimmunoprecipitations were not affected by the state of receptor phosphorylation or cotransfection of arrestin-3. Confocal laser microscopy showed that APLP1 causes a considerable shift of the alpha2A-adrenergic receptor localization from plasma membrane to intracellular compartments. Furthermore, cotransfection of alpha2A-adrenergic receptor and APLP1 into HEK293 cells significantly increased norepinephrine mediated inhibition of adenylate cyclase activity. These results suggest a possible role of APLP1 in regulation of alpha2A-adrenergic receptor trafficking. Moreover, we speculate that this interaction may present one mechanism by which alpha2-adrenergic receptor agonists exert their neuroprotective effects.
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PMID:Interaction of the amyloid precursor like protein 1 with the alpha2A-adrenergic receptor increases agonist-mediated inhibition of adenylate cyclase. 1653 Oct 6

After stimulation with agonist, G protein coupled receptors (GPCR) undergo conformational changes that allow activation of G proteins to transduce the signal, followed by phosphorylation by kinases and arrestin binding to promote receptor internalization. Actual paradigm, based on a study of GPCR-A/rhodopsin family, suggests that a network of interactions between conserved residues located in transmembrane (TM) domains (mainly TM3, TM6 and TM7) is involved in the molecular switch leading to GPCR activation. We evaluated in CHO cells expressing the VPAC(1) receptor the role of the third transmembrane helix in agonist signalling by point mutation into Ala of the residues highly conserved in the secretin-family of receptors: Y(224), N(229), F(230), W(232), E(236), G(237), Y(239), L(240). N(229)A VPAC(1) mutant was characterized by a decrease in both potency and efficacy of VIP stimulated adenylate cyclase activity, by the absence of agonist stimulated [Ca(2+)](i) increase, by a preserved receptor recognition of agonists and antagonist and by a preserved sensitivity to GTP suggesting the importance of that residue for efficient G protein activation. N(229)D mutant was not expressed at the membrane, and the N(229)Q with a conserved mutation was less affected than the A mutant. Agonist stimulated phosphorylation and internalization of N(229)A and N(229)Q VPAC(1) were unaffected. However, the re-expression of internalized mutant receptors, but not that of the wild type receptor, was rapidly reversed after VIP washing. Receptor phosphorylation, internalization and re-expression may be thus dissociated from G protein activation and linked to another active conformation that may influence its trafficking. Mutation of that conserved amino acid in VPAC(2) could be investigated only by a conservative mutation (N(216)Q) and led to a receptor with a low VIP stimulation of adenylate cyclase, receptor phosphorylation and internalization. This indicated the importance of the conserved N residue in the TM3 of that family of receptors.
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PMID:Asn229 in the third helix of VPAC1 receptor is essential for receptor activation but not for receptor phosphorylation and internalization: comparison with Asn216 in VPAC2 receptor. 1665 Sep 65

The melanocortin 3-receptor is involved in regulating energy metabolism, body fluid composition and inflammatory responses. Melanocortin receptors function by activating membrane bound adenylate cyclase. However, the literature reports indicate that some G protein coupled receptors (GPCRs) can also activate mitogen activated protein kinase (MAPK) or phosphoinositide 3 kinase (PI3K) signaling pathways consequent to their endocytosis. These studies were undertaken to evaluate the role of these pathways in MC3R signaling in brain-stem neuronal cells. Recruitment of arrestins is implicated in the activation of secondary pathways by GPCRs and our data shows the colocalization of either arrestin B1 or B2 with MC3R in endosomes. An alteration in PKB phosphorylation pattern was observed in MC3R expressing cells independent of agonist stimulation. MC3R transfectants exhibited increased proliferation rates and inhibition of PKB pathway with triciribine abrogated cell proliferation in both vector control and MC3R transfectants. PKB is constitutively active in proliferating CAD cells but could be further activated by culturing the cells in differentiation medium. These studies suggest that the AKT/PKB pathway plays an important role in the proliferation of CAD cells and suggest a link between MC3R and cell growth pathways that may involve the alteration of AKT/PKB signaling pathway.
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PMID:Endosomal colocalization of melanocortin-3 receptor and beta-arrestins in CAD cells with altered modification of AKT/PKB. 1829 23


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