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154. Gi-mediated activation of the p21ras-mitogen-activated protein kinase pathway by alpha 2-adrenergic receptors expressed in fibroblasts

Author

Jacqueline Alblas, Ej, Corven, Pl, Hordijk, Milligan G, and Wh, Moolenaar

Subjects
Fibroblasts, Transfection, Models, Biological, Recombinant Proteins, Cell Line, Rats, Enzyme Activation, Proto-Oncogene Proteins p21(ras), Kinetics, Pertussis Toxin, GTP-Binding Proteins, Receptors, Adrenergic, alpha-2, Calcium-Calmodulin-Dependent Protein Kinases, Animals, Humans, Virulence Factors, Bordetella, Phosphorylation, Signal Transduction
Abstract

The alpha 2-adrenergic receptors are linked to inhibition of adenylylcyclase and, under certain circumstances, to stimulation of phospholipid hydrolysis via pertussis toxin-sensitive G proteins. Here we show that alpha 2-adrenergic receptors can couple to an alternative signaling pathway. When expressed in Rat-1 cells, stimulation of the alpha 2A receptor, which couples to Gi2 and Gi3, causes rapid, transient activation of the protooncogene product p21ras as measured by an increase in the amount of bound GTP. Furthermore, alpha 2A receptor stimulation causes rapid phosphorylation of the p42 mitogen-activated protein (MAP) kinase. Pertussis toxin completely inhibits both p21ras activation and MAP kinase phosphorylation, but both responses appear to be independent of adenylylcyclase inhibition or phospholipase stimulation. Thus, alpha 2-adrenergic receptors can couple to the p21ras-MAP kinase pathway via Gi, which may explain the mitogenic potential of alpha 2 agonists in certain cell types; together with previous results, these findings further suggest that activation of this pivotal signaling pathway may be a common event in the action of Gi-coupled receptors.

Published
1993

155. G(i)-mediated activation of the p21(ras)-mitogen-activated protein kinase pathway by α2-adrenergic receptors expressed in fibroblasts

Author

Alblas, J., Van Corven, E. J., Hordijk, P. L., Milligan, G., Moolenaar, W. H., and Physiology

Abstract

The α2-adrenergic receptors are linked to inhibition of adenylylcyclase and, under certain circumstances, to stimulation of phospholipid hydrolysis via pertussis toxin-sensitive G proteins. Here we show that α2-adrenergic receptors can couple to an alternative signaling pathway. When expressed in Rat-1 cells, stimulation of the α(2A) receptor, which couples to G(i2) and G(i3), causes rapid, transient activation of the protooncogene product p21(ras) as measured by an increase in the amount of bound GTP. Furthermore, α(2A) receptor stimulation causes rapid phosphorylation of the p42 mitogen- activated protein (MAP) kinase. Pertussis toxin completely inhibits both p21(ras) activation and MAP kinase phosphorylation, but both responses appear to be independent of adenylylcyclase inhibition or phospholipase stimulation. Thus, α2-adrenergic receptors can couple to the p21(ras)-MAP kinase pathway via G(i), which may explain the mitogenic potential of α2 agonists in certain cell types; together with previous results, these findings further suggest that activation of this pivotal signaling pathway may be a common event in the action of G(i)-coupled receptors.

Published
1993

165. Transfluxor circuit amplifies sensing current for computer memories

Author

Milligan, G. C

Subjects
Electronic Components And Circuits
Abstract

To transfer data from the magnetic memory core to an independent core, a reliable sensing amplifier has been developed. Later the data in the independent core is transferred to the arithmetical section of the computer.

Published
1964

166. Digital data command bus

Author

Milligan, G. C

Subjects
Electronic Components And Circuits
Abstract

Command bus constructed from coaxial cable has short segments of its outer jacket and shield removed and replaced with small ferrite cores carrying multiturn windings connected to decoder. Device reduces number of wire pairs required to communicate command data to systems and subsystems.

Published
1973

167. Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/ FFA1 and GPR120/ FFA4.

Author

Milligan, G, Alvarez ‐ Curto, E, Watterson, K R, Ulven, T, and Hudson, B D

Subjects
*LIGANDS (Biochemistry), *FREE fatty acids, *G protein coupled receptors, *GENE expression, *INSULIN, *HOMEOSTASIS
Abstract

The free fatty acid receptors ( FFA) 1 (previously designated GPR40) and FFA4 (previously GPR120) are two GPCRs activated by saturated and unsaturated longer-chain free fatty acids. With expression patterns and functions anticipated to directly or indirectly promote insulin secretion, provide homeostatic control of blood glucose and improve tissue insulin sensitivity, both receptors are being studied as potential therapeutic targets for the control of type 2 diabetes. Furthermore, genetic and systems biology studies in both humans and mouse models link FFA4 receptors to diabetes and obesity. Although activated by the same group of free fatty acids, FFA1 and FFA4 receptors are not closely related and, while the basis of recognition of fatty acids by FFA1 receptors is similar to that of the short-chain fatty acid receptors FFA2 and FFA3, the amino acid residues involved in endogenous ligand recognition by FFA4 receptors are more akin to those of the sphingosine 1 phosphate receptor S1 P1. Screening and subsequent medicinal chemistry programmes have developed a number of FFA1 receptor selective agonists that are effective in promoting insulin secretion in a glucose concentration-dependent manner, and in lowering blood glucose levels. However, the recent termination of Phase III clinical trials employing TAK-875/fasiglifam has caused a setback and raises important questions over the exact nature and mechanistic causes of the problems. Progress in the identification and development of highly FFA4 receptor-selective pharmacological tools has been less rapid and several issues remain to be clarified to fully validate this receptor as a therapeutic target. Despite this, the ongoing development of a range of novel ligands offers great opportunities to further unravel the contributions of these receptors. Linked Articles This article is part of a themed section on 5th BPS Focused Meeting on Cell Signalling. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

Published
2015
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171. G-proteins and the inositol cycle in Dictyostelium discoideum

Author

Bominaar, Anthony, van der Kaay, Jeroen, Kesbeke, F., Snaarjagalska, BE., van Haastert, Peter, MILLIGAN, G, WAKELAM, MJO, KAY, J, and University of Groningen

Subjects
MUTANTS, 1,4,5-TRISPHOSPHATE, SIGNAL TRANSDUCTION, SUBUNITS
Abstract

The inositol cycle in Dictyostelium disocideum was studied both in vitro and in vivo. The results are compared to the inositol cycle as it is known from higher eukaryotes. Although there is a strong resemblance the cycles are different at some essential points. In comparison to higher eukaryotes, in the cycle in D. discoideum the inositol 1,4,5-trisphosphate [Ins(1,4,5) P3] kinase appears to be absent and there are additional phosphatases which hydrolyse Ins(1,4,5)P3 via inositol 4,5-bisphosphate [Ins(4,5)P2] to inositol 4-phosphate (Ins4P). The function of the receptor-stimulated inositol cycle was elucidated using mutants from the fgd A complementation group, which are defective in the G-protein alpha-subunit, responsible for the activation of phosphoinositidase C. These mutants show defects in both chemotaxis and differentiation, suggesting that the stimulation of phosphoinositidase C is the major sensory transduction pathway in D. discoideum.

Published
1990

178. The Role of GPCR Dimerisation/Oligomerisation in Receptor Signalling.

Author

Bourne, H., Horuk, R., Kuhnke, J., Michel, H., Milligan, G., Canals, M., Pediani, J. D., Ellis, J., and Lopez-Gimenez, J. F.

Abstract

A wide range of techniques have been employed to examine the quaternary structure of G-protein-coupled receptors (GPCRs). Although it is well established that homo-dimerisation is common, recent studies have sought to explore the physical basis of these interactions and the role of dimerisation in signal transduction. Growing evidence hints at the existence of higher-order organisation of individual GPCRs and the potential for hetero-dimerisation between pairs of co-expressed GPCRs. Here we consider how both homo-dimerisation/oligomerisation and hetero-dimerisation can regulate signal transduction through GPCRs and the potential consequences of this for function of therapeutic medicines that target GPCRs. Hetero-dimerisation is not the sole means by which co-expressed GPCRs may regulate the function of one another. Heterologous desensitisation may be at least as important and we also consider if this can be the basis for physiological antagonism between pairs of co-expressed GPCRs. Although there may be exceptions (Meyer et al. 2006), a great deal of recent evidence has indicated that most G-protein-coupled receptors (GPCRs) do not exist as monomers but rather as dimers or, potentially, within higher-order oligomers (Milligan 2004b; Park et al. 2004). Support for such models has been provided by a range of studies employing different approaches, including co-immunoprecipitation of differentially epitope-tagged but co-expressed forms of the same GPCR, co-operativity in ligand binding and a variety of resonance energy transfer techniques (Milligan and Bouvier 2005). Only for the photon receptor rhodopsin has the organisational structure of a GPCR been studied in situ. The application of atomic force microscopy to murine rod outer segment discs indicated that rhodopsin is organised in a series of parallel arrays of dimers (Liang et al. 2003) and based on this, molecular models were constructed to try to define and interpret regions of contact between the monomers (Fotiadis et al. 2004). Only for relatively few other GPCRs are details of the molecular basis of dimerisation available but within this limited data set, recent studies on the dopamine D2 receptor suggest a means by which information on the binding of an agonist can be transmitted between the two elements of the dimer via the dimer interface (Guo et al. 2005). Although the availability of cDNAs encoding molecularly defined GPCRs has allowed high-throughput screening for ligands that modulate GPCR function, this is performed almost exclusively in heterologous cell lines transfected to express only the specific GPCR of interest. Given that the human genome contains some 400-450 genes encoding non-chemosensory GPCRs, it is clear that any individual cell of the body may express a considerable number of GPCRs. Interactions between these, either via hetero-dimerisation, via heterologous desensitisation or via the integration of downstream signals can potentially alter the pharmacology, sensitivity and function of receptor agonists and hence produce varied responses. In this article, we will use specific examples to consider the role of homo-dimerisation/oligomerisation in GPCR function and whether either direct hetero-dimerisation or heterologous desensitisation between pairs of co-expressed GPCRs affects the function of the receptor pairs. [ABSTRACT FROM AUTHOR]

Published
2007
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180. The novel antidepressant, S35966, is a mixed serotonin and noradrenaline reuptake inhibitor and an antagonist at α2-adrenoceptors

Author

Gobert, A., primary, Cussac, D., additional, Lejeune, F., additional, Newman-Tancredi, A., additional, Audinot, V., additional, Boutin, J.A., additional, Carr, C., additional, Milligan, G., additional, Rivet, J.-M., additional, Brocco, M., additional, Dekeyne, A., additional, Lacoste, J.-M., additional, Cordi, A., additional, and Millan, M.J., additional

Published
2002
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184. Geomorphology for Engineers

Author

Fookes, P. G., Lee, E. Mark, Milligan, G. C., Fookes, P. G., Lee, E. Mark, and Milligan, G. C.

Subjects
Geomorphology, Engineering geology
Abstract

This book presents a worldview of geomorphology for engineers and other professionals on the near-surface engineering problems associated with the various landscapes.

Published
2005

193. Book reviewsLowlands development and management. MiuraN.MadhavM. R. and KogaK. (editors). Rotterdam Balkema, 1994. ISBN 9 05 410603 4. £64Soft soil properties and testing methods. AmaryanL. S. (translated from the Russian and edited by R. B. Zeidler). Rotterdam: Balkema, 1993, 180 pp. ISBN 9 05 410134 2. £46The practice of soil reinforcing in Europe. IngoldT. S. (editor). London: Thomas Telford, 1995, 309 pp. ISBN 0 72 772083 X. £55Barrier containment technologies for environmental remediation applications. Rumer R. R. and Ryan M. E. (editors). New York: Wiley, 1995, 170 pp. ISBN 0 47 113272 1. £45

Author

Stoner, R. F., primary, Butcher, A. P., additional, Milligan, G. W. E., additional, and Tedd, P., additional

Published
1997
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