Prostanoids are the cyclooxygenase metabolites of arachidonic acid and include prostaglandin (PG) D2, PGE2, PGF2α, PGI2, and thromboxne A2. They are synthesized and released upon cell stimulation and act on cells in the vicinity of their synthesis to exert their actions. Receptors mediating the actions of prostanoids were recently identified and cloned. They are G protein-coupled receptors with seven transmembrane domains. There are eight types and subtypes of prostanoid receptors that are encoded by different genes but as a whole constitute a subfamily in the superfamily of the rhodopsin-type receptors. Each of the receptors was expressed in cultured cells, and its ligand-binding properties and signal transduction pathways were characterized. Moreover, domains and amino acid residues conferring the specificities of ligand binding and signal transduction are being clarified. Information also is accumulating as to the distribution of these receptors in the body. It is also becoming clear for some types of ...

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Prostanoid Receptors: Structures, Properties, and Functions

Cyclooxygenases metabolize arachidonate to five primary prostanoids: PGE2, PGF2α, PGI2, TxA2, and PGD2. These autacrine lipid mediators interact with specific members of a family of distinct G-protein-coupled prostanoid receptors, designated EP, FP, IP, TP, and DP, respectively. Each of these receptors has been cloned, expressed, and characterized. This family of eight prostanoid receptor complementary DNAs encodes seven transmembrane proteins which are typical of G-protein-coupled receptors and these receptors are distinguished by their ligand-binding profiles and the signal transduction pathways activated on ligand binding. Ligand-binding selectivity of these receptors is determined by both the transmembrane sequences and amino acid residues in the putative extracellular-loop regions. The selectivity of interaction between the receptors and G proteins appears to be mediated at least in part by the C-terminal tail region. Each of the EP1, EP3, FP, and TP receptors has alternative splice variants describe...

Prostanoid receptors: subtypes and signaling.

Microtubules and signal transduction.

The three-dimensional structure of erabutoxin b, a neurotoxin in the venom of the sea snake Laticauda semifasciata, has been determined from a 2.75 A resolution electron density map. Erabutoxin b is one of a family of snake venom neurotoxins, all low-molecular-weight proteins, which block neuromuscular transmission at the postsynaptic membrane. They specifically inhibit the acetylcholine receptor. The molecular shape is that of a shallow elongated saucer with a footed stand formed by the six-membered ring at the COOH-terminal end. The central core of the molecule is an assembly of four disulfide bridges. Three long chain loops emerge as broad fronds from the core region. Approximately 40% of the main chain is organized into a twisted antiparallel beta-pleated sheet of five short strands. In 28 snake venom neurotoxins of established sequence which inhibit the acetylcholine receptor, the four disulfide bridges and seven other residues remain invariant. Three substitution positions conserve residue type. In one wing of the molecule, there is a broad shallow depression which may characterize the reactive site. It is populated by the sevent invariant residues and two of the three type conserved residues. This region is "anchored" on the undersurface of the molecule by the hydroxyl group of Ser-9, the remaining conservatively substituted residue.

Three dimensional structure of erabutoxin b neurotoxic protein: inhibitor of acetylcholine receptor.

Current view on the structure-function relationship of postsynaptic neurotoxins from snake venoms.

Chemical modification of the tryptophan residue in cobratoxin.

Prostaglandin (PG) E2 binds to PGE receptor EP3 subtype and induces Gi activity. To assess the role of the interaction of the carboxylic acid group of agonists and its putative binding site, Arg-309 in the seventh transmembrane domain of EP3alpha receptor, in receptor activation, we have mutated the positively charged Arg-309 to the polar but uncharged Gln (EP3alpha-R309Q) and Asn (EP3alpha-R309N), and to the non-polar Leu (EP3alpha-R309L). Wild-type, EP3alpha-R309Q and EP3alpha-R309N receptors showed high-affinity binding for PGE2, but the EP3alpha-R309L receptor showed very-low-affinity binding. Guanosine 5'-[gamma-thio]triphosphate increased the PGE2 binding to the wild-type receptor, decreased the binding to EP3alpha-R309Q and EP3alpha-R309N receptors, but did not affect that to the EP3alpha-R309L receptor. Furthermore we examined the Gi activities of two types of EP3 agonist, TEI-3356 with a negatively charged carboxylic acid, and TEI-4343, a methyl ester of TEI-3356 with an uncharged but polar group, towards those receptors. Both agonists inhibited the forskolin-stimulated cAMP formation in wild-type, EP3alpha-R309Q and EP3alpha-R309N receptors in the same concentration-dependent manner, but the agonists showed a very low inhibition of EP3alpha-R309L receptor. These findings demonstrate that the hydrogen-bonding interaction of EP3 agonists and residue 309 in the seventh transmembrane domain of the EP3alpha receptor is sufficient for the functional activation of the EP3alpha receptor.

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Functional interaction of the carboxylic acid group of agonists and the arginine residue of the seventh transmembrane domain of prostaglandin E receptor EP3 subtype.

The key amino acid residue of prostaglandin EP3 receptor for governing G protein association and activation steps.

Characterization of Functional Interaction of Carboxylic Acid Group of Agonists and Arginine of the Seventh Transmembrane Domains of Four Prostaglandin E Receptor Subtypes

Chang-sheng Chang

Papers

Chemical modification of the tryptophan residue in cobratoxin.

Functional interaction of the carboxylic acid group of agonists and the arginine residue of the seventh transmembrane domain of prostaglandin E receptor EP3 subtype.

The key amino acid residue of prostaglandin EP3 receptor for governing G protein association and activation steps.

Characterization of Functional Interaction of Carboxylic Acid Group of Agonists and Arginine of the Seventh Transmembrane Domains of Four Prostaglandin E Receptor Subtypes

Cytoskeletal regulation of the signal transduction of prostaglandin EP4 receptor