Regulation of colonic apical potassium (BK) channels by cAMP and somatostatin

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 297; no. 1; pp. G159 - G167
• Main Authors: Perry, M D, Sandle, G I
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.07.2009
• Subjects: Animals; Catalytic Domain; Cell Polarity; Cells; Colon; Colon - cytology; Colon - drug effects; Colon - enzymology; Colon - metabolism; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Diarrhea; Enzyme Activation; Enzyme Activators - pharmacology; Enzyme Inhibitors - pharmacology; Glycoproteins; Hormones and Signaling; Humans; In Vitro Techniques; Intestinal Mucosa - cytology; Intestinal Mucosa - drug effects; Intestinal Mucosa - enzymology; Intestinal Mucosa - metabolism; Ion Channel Gating - drug effects; Kinases; Kinetics; Large-Conductance Calcium-Activated Potassium Channels - metabolism; Male; Membrane Potentials; Peptides; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Potassium; Potassium - metabolism; Potassium, Dietary - administration & dosage; Protein Processing, Post-Translational - drug effects; Protein Tyrosine Phosphatases - metabolism; Rats; Rats, Wistar; Somatostatin - metabolism
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00132.2009

High-conductance apical K+ (BK) channels are present in surface colonocytes of mammalian (including human) colon. Their location makes them well fitted to contribute to the excessive intestinal K(+) losses often associated with infective diarrhea. Since many channel proteins are regulated by phosphorylation, we evaluated the roles of protein kinase A (PKA) and phosphatases in the modulation of apical BK channel activity in surface colonocytes from rat distal colon using patch-clamp techniques, having first increased channel abundance by chronic dietary K+ enrichment. We found that PKA activation using 50 micromol/l forskolin and 5 mmol/l 3-isobutyl-1-methylxanthine stimulated BK channels in cell-attached patches and the catalytic subunit of PKA (200 U/ml) had a similar effect in excised inside-out patches. The antidiarrheal peptide somatostatin (SOM; 2 micromol/l) had a G protein-dependent inhibitory effect on BK channels in cell-attached patches, which was unaffected by pretreatment with 10 micromol/l okadaic acid (an inhibitor of protein phosphatase type 1 and type 2A) but completely prevented by pretreatment with 100 micromol/l Na+ orthovanadate and 10 micromol/l BpV (inhibitors of phosphoprotein tyrosine phosphatase). SOM also inhibited apical BK channels in surface colonocytes in human distal colon. We conclude that cAMP-dependent PKA activates apical BK channels and may enhance colonic K+ losses in some cases of secretory diarrhea. SOM inhibits apical BK channels through a phosphoprotein tyrosine phosphatase-dependent mechanism, which could form the basis of new antidiarrheal strategies.