β1, β2, and β3 adrenoceptors and Na+/H+ exchanger regulatory factor 1 expression in human bronchi and their modifications in cystic fibrosis.
To date, three β-adrenoceptor (β-AR) subtypes have been identified, but only β(1)-ARs and β(2)-ARs have been characterized in human lungs. Moreover, β(2)-ARs physically interact with the cystic fibrosis transmembrane conductance regulator (CFTR) through the Na(+)/H(+) Exchanger Regulatory Factor 1 (NHERF1) protein. β(3)-ARs, which stimulate CFTR activity in transfected cells, have not been identified in human lungs. This study aimed (1) to characterize the presence of β-AR subtypes, especially β(3)-AR, in human bronchi, and (2) to compare their expression as well as that of NHERF1 in non-cystic fibrosis (CF) versus advanced CF lung samples. In human non-CF bronchi, β(1)-AR, β(2)-AR, β(3)-AR, and NHERF1 transcripts and proteins were expressed mainly in bronchial epithelial cells. Those results were strengthened by the native expression of β(1)-AR, β(2)-AR, and β(3)-AR in a human epithelial cell line, 16HBE14o(-). All β-AR subtypes stimulated CFTR activity. In CF bronchi, we demonstrated β(1)-AR and β(3)-AR overexpression, and NHERF1 and β(2)-AR underexpression. The origin of this protein remodeling (involving the physical or functional absence of CFTR, infection, inflammation, or high adrenergic tone) deserves further investigation. These results evidence for the first time, to the best of our knowledge, the presence of β(3)-ARs in human bronchi, and suggest their usefulness as a putative new pharmacologic target in lung diseases where fluid homeostasis is altered. Furthermore, NHERF1 may be a new therapeutic target in patients with CF, to facilitate the trafficking of mutated CFTR to plasma membrane.
Bossard
Florian
F
INSERM, UMR-915, l'Institut du Thorax, IRT-UN, 8 Quai Moncousu, Nantes, France.
Silantieff
Emilie
E
Lavazais-Blancou
Emmanuelle
E
Robay
Amal
A
Sagan
Christine
C
Rozec
Bertrand
B
Gauthier
Chantal
C
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011224:Prazosin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D053778:Thiazolidines / Q000494:pharmacology; D055815:Young Adult
C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; C547787:ADRB1 protein, human; D000318:Adrenergic beta-Agonists; D001565:Benzoates; C505032:CFTR protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D017923:Sodium-Hydrogen Exchangers; D053778:Thiazolidines; C093376:sodium-hydrogen exchanger regulatory factor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D004280:Dobutamine; D000420:Albuterol; D011224:Prazosin