Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets.
Retinoid X receptors (RXRs) are important transcriptional nuclear hormone receptors, acting as either homodimers or the binding partner for at least one fourth of all the known human nuclear receptors. Functional nongenomic effects of nuclear receptors are poorly understood; however, recently peroxisome proliferator-activated receptor (PPAR) gamma, PPARbeta, and the glucocorticoid receptor have all been found active in human platelets. Human platelets express RXRalpha and RXRbeta. RXR ligands inhibit platelet aggregation and TXA(2) release to ADP and the TXA(2) receptors, but only weakly to collagen. ADP and TXA(2) both signal via the G protein, Gq. RXR rapidly binds Gq but not Gi/z/o/t/gust in a ligand-dependent manner and inhibits Gq-induced Rac activation and intracellular calcium release. We propose that RXR ligands may have beneficial clinical actions through inhibition of platelet activation. Furthermore, our results demonstrate a novel nongenomic mode for nuclear receptor action and a functional cross-talk between G-protein and nuclear receptor signaling families.
Moraes
Leonardo A
LA
Cardiac, Vascular and Inflammation Research, William Harvey Research Institute, Barts and the London, Queen Mary University of London, Charterhouse Square, London, UK.
Swales
Karen E
KE
Wray
Jessica A
JA
Damazo
Amilcar
A
Gibbins
Jonathan M
JM
Warner
Timothy D
TD
Bishop-Bailey
David
D
D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D049230:Retinoid X Receptor beta / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism
D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta; D013928:Thromboxane A2; D051057:Proto-Oncogene Proteins c-akt; D043802:GTP-Binding Protein alpha Subunits, Gq-G11