Control of basal CFTR gene expression by bicarbonate-sensitive adenylyl cyclase in human pulmonary cells.
The CFTR protein, encoded by the gene whose mutations induce Cystic Fibrosis, is an anion channel devoted mainly to chloride and bicarbonate transmembrane transport, but which also regulates transport of several other ions. Moreover, it is implicated in the cell response to inflammation, and, reciprocally, cftr gene expression is modulated by inflammatory stimuli and transduction pathways. Looking for a control of CFTR expression by ionic conditions, we investigated the effect of altered extracellular bicarbonate ion concentration on CFTR expression in human pulmonary Calu-3 cells. We found that basal cftr gene transcription is enhanced when extracellular HCO(3)(-) concentration increases from 0 to 25 mmol/l. The transduction pathway controlled by these extracellular [HCO(3)(-)] variations includes cAMP production linked to the stimulation of soluble adenylyl cyclase (sAC), and nuclear accumulation of the transcription factor, CREB. Basal membrane content in CFTR protein exhibits the same variations as cftr mRNA in cells incubated in the presence of extracellular [HCO(3)(-)] between 0 and 25 mmol/l, and is also decreased by inhibiting sAC in the presence of HCO(3)(-). These results show that bicarbonate-controlled sAC stimulation must be taken into account in cell physiology and that basal CFTR expression depends on an ionic parameter.
Baudouin-Legros
Maryvonne
M
Inserm, U845, Paris, F-75015, Université Paris V-Paris Descartes, Faculté de Médecine René Descartes, Paris, F-75075, France. legroscommat@necker.fr
Hamdaoui
Nabila
N
Borot
Florence
F
Fritsch
Janine
J
Ollero
Mario
M
Planelles
Gabrielle
G
Edelman
Aleksander
A
D000262:Adenylyl Cyclases / Q000378:metabolism*; D001639:Bicarbonates / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D001639:Bicarbonates; D017362:Cyclic AMP Response Element-Binding Protein; D010750:Phosphoproteins; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D000262:Adenylyl Cyclases