Genetic Manipulation of Cardiac K ⁺ Channel Function in Mice

Abstract

Abstract-In the mammalian myocardium, potassium (K ϩ ) channels control resting potentials, action potential waveforms, automaticity, and refractory periods and, in most cardiac cells, multiple types of K ϩ channels that subserve these functions are expressed. Molecular cloning has revealed the presence of a large number of K ϩ channel pore forming (␣) and accessory (␤) subunits in the heart, and considerable progress has been made recently in defining the relationships between expressed K ϩ channel subunits and functional cardiac K ϩ channels. To date, more than 20 mouse models with altered K ϩ channel expression/functioning have been generated using dominant-negative transgenic and targeted gene deletion approaches. In several instances, the genetic manipulation of K ϩ channel subunit expression has revealed the role of specific K ϩ channel subunit subfamilies or individual K ϩ channel subunit genes in the generation of myocardial K ϩ channels. In other cases, however, the phenotypic consequences have been unexpected. This review summarizes what has been learned from the in situ genetic manipulation of cardiac K ϩ channel functioning in the mouse, discusses the limitations of the models developed to date, and explores the likely directions of future research.

A Simple Technique for Isolating Healthy Heart Cells from Mouse Models

“…In these cells, one can take advantage of the versatility of recent genetic engineering technology [1] and also of the accuracy of single-cell measurement techniques such as patch-clamp and Ca 2+ imaging. So far, molecular mechanisms of fundamental heart functions, such as excitation-contraction coupling, action potential shaping, and β-adrenergic signaling, have been successfully unveiled by using single heart cells of mouse models [2][3][4][5][6][7]. Moreover, these cells also provide a convenient platform for analyzing pathogenic mechanisms and the pathophysiology of hereditary heart diseases in molecular detail [8,9].…”

Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K + channel subunit

“…Early success in suppressing excitability has involved the targeted expression of modified ion channels or receptors (10,15,16). A promising approach for enhancing electrical activity involves the dominantnegative suppression of K ϩ currents involved in membrane repolarization and excitability (17,18).…”

Effects of diltiazem and propafenone on the inactivation and recovery kinetics of fKv1.4 channel currents expressed in Xenopus oocytes

“…It has been reported that the cardiac action potentials in mice were lengthened by 10 nmol/L diltiazem, a finding that may be explained by diltiazem-induced blockade of the I to (slow) currents generated by the Kv1.4 channel [33] . The Kv1.4 channel, as the major component of I to (slow), which in turn is a major contributor to phase 1 and the early part of phase 2 of the action potential, plays an important role in the repolarization of the endocardial region of the left ventricle [34] .…”