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  • Title: Pharmacological rescue of human K(+) channel long-QT2 mutations: human ether-a-go-go-related gene rescue without block.
    Author: Rajamani S, Anderson CL, Anson BD, January CT.
    Journal: Circulation; 2002 Jun 18; 105(24):2830-5. PubMed ID: 12070109.
    Abstract:
    BACKGROUND: Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K(+) current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K(+) current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue. Methods and Results- We postulated that drug molecules modified to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of trafficking-defective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is approximately 350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block. CONCLUSIONS: Pharmacological rescue can occur without channel block. This could represent a new antiarrhythmic paradigm in the treatment of some trafficking-defective LQT2 mutations.
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