Control of the cystic fibrosis transmembrane conductance regulator by alphaG(i) and RGS proteins.
The cystic fibrosis transmembrane conductance regulator (CFTR) has been shown previously to be regulated by inhibitory G proteins. In the present study, we demonstrate inhibition of CFTR by alphaG(i2) and alphaG(i1), but not alphaG(0), in Xenopus oocytes. We further examined whether regulators of G protein signaling (RGS) proteins interfere with alphaG(i)-dependent inhibition of CFTR. Activation of CFTR by IBMX and forskolin was attenuated in the presence of alphaG(i2), indicating inhibition of CFTR by alphaG(i2) in Xenopus oocytes. Coexpression of the proteins RGS3 and RGS7 together with CFTR and alphaG(i2) partially recovered activation by IBMX/forskolin. 14-3-3, a protein that is known to interfere with RGS proteins, counteracted the effects of RGS3. These data demonstrate the regulation of CFTR by alphaG(i) in Xenopus oocytes. Because RGS proteins interfere with the G protein-dependent regulation of CFTR, this may offer new potential pathways for pharmacological intervention in cystic fibrosis.
Department of Physiology and Pharmacology, University of Queensland, St. Lucia, Queensland, 4072, Australia.
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R
Schreiber
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Kindle
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T
Benzing
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Walz
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Kunzelmann
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D048948:14-3-3 Proteins; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D018118:Chloride Channels / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000502:physiology*; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D020710:RGS Proteins / Q000235:genetics / Q000502:physiology*; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D012097:Repressor Proteins; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000502:physiology; D014982:Xenopus laevis
D048948:14-3-3 Proteins; D000067956:Adenylyl Cyclase Inhibitors; C505032:CFTR protein, human; D018118:Chloride Channels; D020690:GTPase-Activating Proteins; D020710:RGS Proteins; C485898:RGS3 protein, human; C492039:RGS7 protein, human; D018075:RNA, Complementary; D012097:Repressor Proteins; C415085:Rgs3 protein, mouse; C437714:Rgs3 protein, rat; C492038:Rgs7 protein, mouse; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D014446:Tyrosine 3-Monooxygenase; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine