INTRACELLULAR PROTONS CONTROL THE AFFINITY OF SKELETAL-MUSCLE ATP-SENSITIVE K-CHANNEL-OPENERS( CHANNELS FOR POTASSIUM)

Levcromakalim, a potential antihypertensive agent, is known to activat e potassium channels dependent on intracellular ATP (K-ATP channels). In inside-out patches excised from frog skeletal muscle, levcromakalim or a related compound, SR 47063, caused a strong and persistent activ ation of K-ATP channels at a cytoplasmic pH of 7.1. However, at pH 6, these activators could no longer affect the K-ATP currents. Conversely , in the continuous presence of activator, lowering pH from 7.1 to 6 r eturned channel activity to its level in pH 6 alone. After wash-out of the activator, recovery from activation took minutes at pH 7.1 but on ly seconds at pH 6, thus ruling out an effect of protons on the activa tors in solution. These experiments suggest that K-channel-activators are unable to bind to their receptor when it is protonated, and more g enerally, they provide evidence at the microscopic level for proton-in duced allosteric modulation of drug-receptor interaction.