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Trypsin activation of atrial muscarinic potassium channels

Trypsin activation of atrial muscarinic potassium channels

American Journal of Physiology 257(1 Part 2): H334-H338

The atrial muscarinic K+ channel normally is opened by the activated G protein, Gk. Based on the assumption that an inactivating particle keeps the channel closed, several protein-modifying agents including trypsin, papain, glyoxal, and phenylglyoxal that remove Na+-channel inactivation were tested. K+ channels were studied in inside-out excised membrane patches from primary cultures of neonatal rat atrial myocytes. Of the agents tested, only trypsin activated muscarinic K+ channels, and it did so irreversibly. Trypsin was effective in the absence of muscarinic agonist or intracellular Mg2+ and guanosine 5'-triphosphate. Heat-denatured trypsin was ineffective, and trypsin inhibitor blocked the effect. Because trypsin is known to inactivate G proteins, the effect was probably on the K+ channel or a structure closely associated with it. Trypsin activation produced single-channel currents in which inward rectification, single-channel conductance, mean open time, and burst duration were indistiguishable from muscarinic activation. Trypsin cleaves proteins at lysine or arginine residues, and the arginine-specific reagents, glyoxal and phenylgloxal, did not activate K+ channels. We conclude that trypsin disrupts an inhibitory gating mechanism that normally holds the channel closed in the absence of activated Gk. The inhibitory gate is physically distinct from the gate that mediates bursting and must contain at least one trypsin cleavage pint located at a lysine residue accessible from the cytoplasmic surface of the cell membrane.

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