Diapositiva 1

1
ON THE MECHANISM OF ACTIVATION AND INHIBITION OF
THE CFTR-MEDIATED IONIC TRANSPORT BY A
7,8-BENZOFLAVONE Chiara Pincin, Loretta Ferrera
and Oscar Moran Istituto di Biofisica, CNR Genova
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Cystic Fibrosis
CF is a recessive genetic disease
characterized by pulmonary, gastrointestinal
disease and reproductive tract disfunction.
CF results from mutations in cystic fibrosis
transmembrane conductance regulator (CFTR) gene.
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The Protein Encoded by the Cystic Fibrosis Gene
Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR)

• A cAMP-dependent Cl- channel
• Two sets of 6 transmembrane
• domains
• Two ATP-binding cassettes

Unique among channels and ABC transporters
(phosphorylated by PKA)
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CFTR-activators a possible CF therapy for type
III (altered gating) mutations?
(µM)
Action of Genistein on G551D mutation
5
CFTR-openers behave different for different CFTR
isoforms
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Genistein
UCCF-029
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UCCF-029 a strong potentiator of CFTR-dependent
Cl- secretion
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UCCF-029 Activity at 12.5 nM
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UCCF-029 Activity at 100 nM
100

80
60
P(o)
40
20
0
Control
UCCF-029
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ATP and UCCF-029 2 different binding sites
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Conclusions

• The UCFF-029 is a potent modulator of CFTR with
  complex effects on channel activity

• Low concentrations of UCCF-029 stimulate CFTR by
  decreasing channel closings

• Higher concentrations of the drug inhibit CFTR
  by decreasing channel
• openings

- The binding site of UCCF-029 and ATP is
different
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