Abstract
Na+ channel blockers such as flecainide have found renewed usefulness in the diagnosis and treatment of two clinical syndromes arising from inherited mutations in SCN5A, the gene encoding the α subunit of the cardiac voltage–gated Na+ channel. The Brugada syndrome (BrS) and the LQT-3 variant of the Long QT syndrome are caused by disease-linked SCN5A mutations that act to change functional and pharmacological properties of the channel. Here we have explored a set of SCN5A mutations linked both to BrS and LQT-3 to determine what disease-modified channel properties underlie distinct responses to the Na+ channel blocker flecainide. We focused on flecainide block that develops with repetitive channel activity, so-called use-dependent block (UDB). Our results indicate that mutation-induced changes in the voltage-dependence of channel availability (inactivation) may act as determinants of flecainide block. The data further indicate that UDB by flecainide requires channel opening, but is not likely due to open channel block. Rather, flecainide appears to interact with inactivation states that follow depolarization-induced channel opening, and mutation-induced changes in channel inactivation will alter flecainide block independent of the disease to which the mutation is linked. Analysis of flecainide block of mutant channels linked to these rare disorders has provided novel insight into the molecular determinants of drug action.
Highlights
Local anesthetic molecules such as lidocaine and flecainide block Naϩ channels and have been used therapeutically to manage cardiac arrhythmias (Rosen et al, 1975; Rosen and Wit, 1983; Wit and Rosen, 1983)
Naϩ channel blockers have again proven useful for diagnosis and treatment of Brugada and LQT-3 syndromes, two inherited diseases linked to mutations in SCN5A, the gene that encodes the ␣ subunit of the cardiac voltage–gated Naϩ channel (Brugada et al, 1999)
The results of our work indicate that flecainide block that develops with repetitive channel activity, so-called use-dependent block (UDB) requires channel opening
Summary
Local anesthetic molecules such as lidocaine and flecainide block Naϩ channels and have been used therapeutically to manage cardiac arrhythmias (Rosen et al, 1975; Rosen and Wit, 1983; Wit and Rosen, 1983). Naϩ channel blockers have again proven useful for diagnosis and treatment of Brugada and LQT-3 syndromes, two inherited diseases linked to mutations in SCN5A, the gene that encodes the ␣ subunit of the cardiac voltage–gated Naϩ channel (Brugada et al, 1999). Naϩ channel blockade by the flecainide is of particular interest as it had been shown to reduce QT prolongation in carriers of some LQT-3 mutations (Brugada et al, 1999), and (Benhorin et al, 2000; Windle et al, 2001)and to evoke ST segment elevation, a hallmark of the Brugada syndrome (BrS),* in patients with a predisposition to the disease (Brugada et al, 2000). Exploration of the relationship between altered channel structure and drug efficacy can provide new insight into molecular determinants of flecainide block of the human cardiac sodium channel
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