Cell signalling through thromboxane A2 receptors.
Thromboxane A2 receptors (TPs) are widely distributed among different organ systems and have been localized on both cell membranes and intracellular structures. Following the initial cloning of this receptor class from human placenta, the deduced amino acid sequence predicted seven-transmembrane spanning regions, four extracellular domains and four intracellular domains, making TP a member of the seven-transmembrane G-protein-coupled receptor (GPCR) super family. A single gene on chromosome 19p13.3 leads to the expression of two separate TP isoforms: TPalpha which is broadly expressed in numerous tissues, and a splice variant termed TPbeta which may have a more limited tissue distribution. Mutagenesis, photoaffinity labelling, and immunological studies have indicated that the ligand binding domains for this receptor may reside in both the transmembrane (TM) and extracellular regions of the receptor protein. In addition, separate studies have provided evidence that this receptor can couple to at least four separate G protein families. As a consequence, TP signalling has been shown to result in a broad range of cellular responses including phosphoinositide metabolism, calcium redistribution, cytoskeletal arrangement, integrin activation, kinase activation, and the subsequent nuclear signalling events involved in DNA synthesis, cell proliferation, cell survival and cell death. While activation of these different signalling cascades can all derive from TP stimulation, the relative signalling preference for a given cascade appears to be both tissue and cell specific. Finally, separate studies have indicated that TP signalling capacity can be both down-regulated by protein kinase activation and up-regulated by GPCR cross-signalling. Thus, the multitude of signalling events which derive from TP activation can themselves be modulated by endogenous cellular messengers.
Huang
Jin-Sheng
JS
Department of Pharmacology, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Avenue (Mail Code 868), Chicago, IL 60612, USA.
Ramamurthy
Santosh K
SK
Lin
Xin
X
Le Breton
Guy C
GC
D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013928:Thromboxane A2 / Q000378:metabolism*
D011448:Prostaglandin Antagonists; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D020928:Mitogen-Activated Protein Kinases; D020962:Heterotrimeric GTP-Binding Proteins