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Transgenic Animals of Enzymes and Receptors in Prostanoid Synthesis and Actions; Phenotypes and Implications in Drug Development

  • Chapter
Transgenic Models in Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 159))

Abstract

Prostanoids, consisting of the prostaglandins (PGs) and the throm- boxanes (TXs), are oxygenated products of C20 unsaturated fatty acids, and include PGD2, PGE 2, PGF2a, PGI2, and TXA2. Precursor fatty acids such as arachidonic acid are liberated from the membrane phospholipids by the action of phospholipase A2 (PLA2) in response to various stimuli. Arachidonic acid thus liberated, for example, is metabolized to prostaglandin H2 (PGH2) by the actions of cyclooxygenase (COX), which is then converted to respective PGs by the respective PG synthases. There are two isoforms of cyclooxygenase known as COX-1 and COX-2. Because aspirin-like nonsteroidal anti-inflammatory drugs exert their actions by inhibiting COX and suppressing prostanoid production, prostanoids are believed to work in physiological and pathophysiological processes inhibited by these drugs such as inflammation, fever, and pain. Prostanoids are released outside of the cells immediately after synthesis, and exert their actions by binding to a G protein-coupled rhodopsin-type receptor on the surface of target cells. There are eight types and subtypes of the prostanoid receptors conserved in mammals from mouse to human. They are the PGD receptor, four subtypes of the PGE receptor, EP1, EP2, EP3, and EP4, the PGF receptor, PGI receptor, and TxA receptor. Genes for several enzymes in prostanoid synthesis such as PLA2 and COX isoforms and genes for the eight types and subtypes of the prostanoid receptors were individually disrupted, and various phenotypes of these knockout mice have been reported. In addition, transgenic mice over-expressing a relevant gene and transfer of such a gene in experimental animals were also reported. In this article, we discuss the phenotypes of these animals in context of prostanoid actions under various physiological and pathophysiological conditions.

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  1. Department of Pharmacology, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan

    S. Narumiya

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  1. Pharmakologisches Institut, Universität Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany

    Stefan Offermanns

  2. Institut für Pharmakologie und Toxikologie der Universität, Versbacher Straße 9, 97078, Germany

    Lutz Hein

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Narumiya, S. (2004). Transgenic Animals of Enzymes and Receptors in Prostanoid Synthesis and Actions; Phenotypes and Implications in Drug Development. In: Offermanns, S., Hein, L. (eds) Transgenic Models in Pharmacology. Handbook of Experimental Pharmacology, vol 159. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18934-0_15

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  • DOI: https://doi.org/10.1007/978-3-642-18934-0_15

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