Phosphorylation-dependent regulation of apical membrane chloride channels in normal and cystic fibrosis airway epithelium.
The observations described herein allow us to make several inferences about PKC and regulation of normal and CF Cl- channels. FIGURE 5 shows a model that summarizes these observations. In this model, for the sake of clarity, we refer to the channel as a single entity, but note that it may consist of multiple subunits and associated proteins. FIGURE 5A shows the channel in an inactivated state following excision from the cell. The channel can be activated by strong membrane depolarization, via an unknown mechanism, or by phosphorylation with PKA or PKC at a low [Ca2+] We speculate that PKA and PKC may phosphorylate and activate the channel at the same site, or region of the channel, because phosphorylation-dependent activation by both is defective in CF. This result suggests that the CF defect might lie in a defective phosphorylation site on the channel, or associated protein, or in the mechanism that converts phosphorylation into a change in channel conformation, such as activation. Activated channels can be inactivated by PKC at a high [Ca2+]. At high [Ca2+], PKC maintains the channel in an inactivated state and it inactivates channels that have been activated by PKC at low [Ca2+], by depolarization, or by PKA. Both activation and inactivation appear to result from phosphorylation; neither can be explained by down-regulation of the channel. There are several possible ways to explain the two opposite effects of PKC on the Cl- channel: different responses may be due to an effect of Ca2+ on the channel, on PKC, or on the interaction between the two.(ABSTRACT TRUNCATED AT 250 WORDS)
Welsh
M J
MJ
Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City 52242.
Li
M
M
McCann
J D
JD
Clancy
J P
JP
Anderson
M P
MP
D001980:Bronchi / Q000378:metabolism*; D018118:Chloride Channels; D002712:Chlorides / Q000502:physiology*; D003550:Cystic Fibrosis / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D014132:Trachea / Q000378:metabolism*
D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D011494:Protein Kinases; D011493:Protein Kinase C