Environmental Differences of a Pyridine Derivative (AU-1421)-Access Sites between (H^+, K^+)-ATPase and (Na^+, K^+)-ATPase

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We investigated the environmental differences of a pyridine derivative-access sites between hog gastric (H^+, K^+)-ATPase and dog kidney (Na^+, K^+)-ATPase. The environmental differences are inferred from the marked contrasts in inhibition properties of (Z)-5-methyl-2-[2-(1-naphthyl) ethenyl]-4-piperidinopyridine hydrochloride (AU-1421) between the two adenosine triphosphatases (ATPases). AU-1421 is a hydrophobic pyridine derivative which inhibits (H^+, K^+)-ATPase and (Na^+, K^+)-ATPase competitively with respect to K^+. AU-1421 inhibition of (Na^+, K^+)-ATPase activity is preincubation time-dependent, pH-independent (pH 6.4-8.4), and hardly reversible by dialysis. These features are opposite to those found with the gastric (H^+, K^+)-ATPase. Furthermore, in the presence of dilute sodium dodecyl sulfate (30-120 μM), the inhibitory potency of AU-1421 for (Na^+, K^+)-ATPase is increased, whereas the inhibitory potency for (H^+, K^+)-ATPase is decreased. These results favor proposals that protonated species of AU-1421 interact with its access-site of (H^+, K^+)-ATPase at the exterior surface of the enzyme molecule by ionic interaction, whereas AU-1421 interacts with its access-site of (Na^+, K^+)-ATPase at the interior domain of the enzyme molecule predominantly by hydrophobic interaction. The differences indicate the existence of a different feature of K^+-access sites between the two ATPases.
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