Sp. Hardy et al., REGULATION OF VOLUME-ACTIVATED CHLORIDE CHANNELS BY PROTEIN-KINASE C-MEDIATED PHOSPHORYLATION OF P-GLYCOPROTEIN, Japanese Journal of Physiology, 44, 1994, pp. 9-15
The multidrug resistance P-glycoprotein (Pgp) transports hydrophobic d
rugs out of cells and has been recently associated with volume-activat
ed chloride channels. Activation of these channels by hypotonic swelli
ng was seen to be prevented by protein kinase C (PKC) in cells express
ing high levels of Pgp by transfection. HeLa cells possess equivalent
chloride currents yet they are not regulated by PKC. HeLa cells do not
express Pgp as assessed by Western blotting. Following transfection o
f HeLa cells with cDNA encoding for Pgp, PKC-dependent suppression of
volume activated chloride currents was observed. PKC regulation in tra
nsiently transfected HeLa cells was abolished by alanine replacement o
f the serine/threonine residues in the consensus phosphorylation sites
of the linker region of Pgp. Replacement of these residues with gluta
mate, to mimic the effect of phosphorylation, mimicked the effects of
PKC on channel activation, These results indicate that overexpression
of Pgp confers PKC-regulation of endogenous volume-activated chloride
channels, More generally they favour a model in which Pgp acts as a re
gulator of volume-activated chloride channels.