Procaine, a state-dependent blocker, inhibits HERG channels by helix residue Y652 and F656 in the S6 transmembrane domain.

ABSTRACT

The article evaluated the inhibitory action of procaine on wild-type and mutated HERG potassium channel current (I(HERG)) to determine whether mutations in the S6 region are important for the inhibition of I(HERG) by procaine. HERG channels (WT, Y652A, and F656A) were expressed in Xenopus laevis oocytes and studied using the standard two-microelectrode voltage-clamp technique. The results revealed that WT HERG is blocked in a concentration-, voltage-, and state-dependent manner by procaine ([IC50] = 34.79 µM). The steady state activation curves slightly move to the negative, while inactivation parameters move to the positive in the presence of procaine. Time-dependent test reveals that voltage-dependent I(HERG) blockade occurs extremely rapidly. Furthermore, the mutation to Ala of Y652 and F656 produce about 11-fold and 18-fold increases in IC50 for I(HERG) blockade, respectively. Simultaneously, for Y652A, the steady state activation and inactivation parameters are shifted to more positive values after perfusion of procaine. Conclusively, procaine state-dependently inhibits HERG channels (WT, Y652A, and F656A). The helix residues Y652 and F656 in the S6 transmembrane domain might play a role in interaction of the drug with the channel.