The cardiac action potential is critical to the production of a synchronized heartbeat. This
electrical impulse is governed by the intricate activity of cardiac ion channels, among them
the cardiac ...voltage-gated potassium (Kv) channels KCNQ1 and hERG as well as the
voltage-gated sodium (Nav) channel encoded by SCN5A. Each channel performs a highly
distinct function, despite sharing a common topology and structural components. These
three channels are also the primary proteins mutated in congenital long QT syndrome
(LQTS), a genetic condition that predisposes to cardiac arrhythmia and sudden cardiac
death due to impaired repolarization of the action potential and has a particular proclivity
for reentrant ventricular arrhythmias. Recent cryo-electron microscopy structures of
human KCNQ1 and hERG, along with the rat homolog of SCN5A and other
mammalian sodium channels, provide atomic-level insight into the structure and
function of these proteins that advance our understanding of their distinct functions in
the cardiac action potential, as well as the molecular basis of LQTS. In this review, the
gating, regulation, LQTS mechanisms, and pharmacological properties of KCNQ1, hERG,
and SCN5A are discussed in light of these recent structural findings.
Cell-volume regulation after hyposmotic swelling is common in transporting epithelial cells. Acute regulatory volume decrease is mediated in several cell types by loss of K(+) and Cl(-) via channels ...either activated by the swelling phenomenon or active in the cell membrane prior to swelling. In the last two decades, it has become clear that many features of cell-volume regulation mediated by ion fluxes vary considerably among cell types. In some instances, the ion channel activation, although demonstrable, is insufficient to account, on the basis of ion fluxes, for the measured cell volume changes. Here we review the case of a salt-transporting epithelium in which hyposmotic cell swelling activates plasma membrane K(+) channels, but at the same time inhibits Cl(-) channels, thus preventing an acute volume-regulatory response. The sequence of events following cell swelling appears to be as follows: K(+) channels are activated by membrane stretch, the cell membrane hyperpolarizes (the voltage moves closer to the K(+) equilibrium potential) and this hyperpolarization reduces the Cl(-) conductance, likely by a reduction in open probability of voltage-sensitive Cl(-) channels. The significance of this phenomenon may be related to the preservation of intracellular Cl(-) rather than cell volume, or to a physiological 'need' to prevent shrinkage of cells stimulated by hormones or other mediators.
