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Membrane depolarization mediates phosphorylation and nuclear translocation of CREB in vascular smooth muscle cells.
Stevenson A, Cartin L, Wellman T, Dick M, Nelson MT, Lounsbury K
Experimental Cell Research. 2001;263( 1):118-30.
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Abstract
Diverse signals have the potential to modulate gene transcription through the Ca2+ and cAMP response element binding protein (CREB) in vascular smooth muscle cells (VSMCs). A key step in the transmission of these signals is import into the nucleus. Here, we provide evidence that the Ran GTPase, which regulates nuclear import, exerts different regulation over PDGF-BB, Ca2+, and cAMP signaling to CREB in VSMCs. PDGF-BB, membrane depolarization, and forskolin increased levels of activated CREB (P-CREB) and c-fos in VSMCs and intact aorta. The calcium channel antagonist nimodipine reduced the level of P-CREB stimulated by membrane depolarization, but not by PDGF-BB or forskolin. Block of Ran-mediated nuclear import, by wheat germ agglutinin or an inactivating Ran mutant (T24N Ran), significantly reduced nuclear P-CREB in response to PDGF-BB or membrane depolarization, but enhanced levels of P-CREB in response to forskolin. Contrary to expectation, block of nuclear import led to the appearance of P-CREB in the cytoplasm after depolarization. Furthermore, blocking nuclear export with leptomycin B reduced P-CREB stimulation by both depolarization and PDGF-BB. These results suggest that translocation of CREB between the nucleus and the cytoplasm provides an important role in CREB activating pathways in VSMCs.
Keyword(s)
Animals; Calcium Signaling; Cells, Cultured; Female; Flow Cytometry; Immunohistochemistry; Microinjections; Models, Biological; Rats; Signal Transduction; Transfection; cytology: Aorta; cytology: Muscle, Smooth, Vascular; drug effects: Active Transport, Cell Nucleus; drug effects: Phosphorylation; genetics: Genes, fos; genetics: ran GTP-Binding Protein; metabolism: Actins; metabolism: Calcium; metabolism: Calcium Channels, L-Type; metabolism: Cell Nucleus; metabolism: Cyclic AMP Response Element-Binding Protein; pharmacology: Calcium Channel Blockers; pharmacology: Cyclic AMP-Dependent Protein Kinases; pharmacology: Forskolin; pharmacology: Nimodipine; pharmacology: Platelet-Derived Growth Factor; physiology: Membrane Potentials