Key result
Mutant HERG channels (Y652A and F656A) were approximately 4-30 times less sensitive to inhibition by bupivacaine, ropivacaine, and mepivacaine than wild-type channels.
Local anesthetics specifically interact with aromatic residues Y652 and F656 in the S6 region of HERG channels, providing a molecular basis for their cardiotoxic side effects.
Supports HERG Y652/F656 as key mediators of local anesthetic cardiotoxicity; hypothesis-generating for safer agents pending in vivo confirmation.
BACKGROUND: Human ether-a-go-go-related gene (HERG) potassium channels constitute a potential target involved in cardiotoxic side effects of amino-amide local anesthetics. The molecular interaction site of these low-affinity blockers with HERG channels is currently unknown. The aim of this study was to determine the effect of the mutations Y652A and F656A in the putative drug binding region of HERG on the inhibition by bupivacaine, ropivacaine, and mepivacaine. METHODS: The authors examined the inhibition of wild-type and mutant HERG channels, transiently expressed in Chinese hamster ovary cells by bupivacaine, ropivacaine, and mepivacaine. Whole cell patch clamp recordings were performed at room temperature. RESULTS: Inhibition of HERG wild-type and mutant channels by the different local anesthetics was concentration dependent, stereoselective, and reversible. The sensitivity decreased in the order bupivacaine > ropivacaine > mepivacaine for wild-type and mutant channels. The mutant channels were approximately 4-30 times less sensitive to the inhibitory action of the different local anesthetics than the wild-type channel. The concentration-response data were described by Hill functions (bupivacaine: wild-type IC50 = 22 +/- 2 microm, n = 38; Y652A IC50 = 95 +/- 5 microm, n = 31). The mutations resulted in a change of the stereoselectivity of HERG channel block by ropivacaine. The potency of the local anesthetics to inhibit wild-type and mutant channels correlated with the lipophilicity of the drug (r > 0.9). CONCLUSIONS: These results indicate that local anesthetics specifically but not exclusively interact with the aromatic residues Y652 and F656 in S6 of HERG channels.
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Siebrands et al. (2005) studied Cardiotoxic side effects of amino-amide local anesthetics (in vitro). Amino-amide local anesthetics (bupivacaine, ropivacaine, mepivacaine) vs. Wild-type HERG channels was evaluated on Inhibition of HERG channels (IC50). Mutant HERG channels (Y652A and F656A) were approximately 4-30 times less sensitive to inhibition by bupivacaine, ropivacaine, and mepivacaine than wild-type channels.
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