Effects of phosphorylation on ion channel function.
A fundamental property of ion channels is their ability to be modulated by intracellular second messenger systems acting via covalent modifications of the channel protein itself. One such important biochemical reaction is phosphorylation on serine, threonine, and tyrosine residues. Ion channels in the kidney are no exception. Moreover, many ion channels, including many amiloride-sensitive epithelial Na+ channels, are subject to modulation by a multiplicity of inputs. For example, renal Na+ channels are not gated by voltage in their unphosphorylated state. However, upon phosphorylation by PKA plus ATP, these channels become voltage-dependent as well as having their open probability increased. Phosphorylation by PKC inhibits channel activity regardless of whether the channel was previously phosphorylated by PKA. Likewise, Na+ channel ADP-ribosylation by PTX overrides the actions of cAMP-dependent phosphorylation. Consistent with this idea is the fact that the phosphorylation sites for PKA and PKC and the ADP-ribosylation sites occur on different polypeptides comprising the channel complex. Epithelial Na+ channel activity is also regulated by methylation, arachidonic acid metabolites, and by interactions with cytoskeletal components. An exciting new age in understanding renal Na+ channel function has begun. Canessa and collaborators [103, 104] and Lingueglia et al [105] have, for the first time, identified by expression cloning an amiloride-sensitive Na+ channel from rat distal colon. The messenger RNA encoding the subunits comprising this channel are expressed in the distal tubule and cortical collecting tubule of the kidney (Rossier, unpublished observations). In addition, our laboratory has successfully cloned a mammalian homologue of this same channel from bovine renal papillary collecting ducts [106].(ABSTRACT TRUNCATED AT 250 WORDS)
Ismailov
I I
II
Department of Physiology and Biophysics, University of Alabama at Birmingham, USA.
Benos
D J
DJ
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008564:Membrane Potentials; D010766:Phosphorylation; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015222:Sodium Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
D015220:Calcium Channels; D004232:Diuretics; D007473:Ion Channels; D015221:Potassium Channels; D015222:Sodium Channels; D000584:Amiloride; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C