Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium

Abstract

In the mammalian heart, Ca2+-independent, depolarization-activated potassium (K+) currents contribute importantly to shaping the waveforms of action potentials, and several distinct types of voltage-gated K+ currents that subserve this role have been characterized. In most cardiac cells, transient outward currents, Ito,f and/or Ito,s, and several components of delayed reactivation, including IKr, IKs, IKur and IK,slow, are expressed. Nevertheless, there are species, as well as cell-type and regional, differences in the expression patterns of these currents, and these differences are manifested as variations in action potential waveforms. A large number of voltage-gated K+ channel pore-forming (alpha) and accessory (beta, minK, MiRP) subunits have been cloned from or shown to be expressed in heart, and a variety of experimental approaches are being exploited in vitro and in vivo to define the relationship(s) between these subunits and functional voltage-gated cardiac K+ channels. Considerable progress has been made in defining these relationships recently, and it is now clear that distinct molecular entities underlie the various electrophysiologically distinct repolarizing K+ currents (i.e. Ito,f, Ito,s, IKr, IKs, IKur, IK,slow, etc.) in myocyardial cells.

Figure 1. Action potential waveforms are variable in different regions of the heart

Schematic representation of the heart; action potential waveforms recorded in different regions of the heart are illustrated. Action potentials are displaced in time to reflect the temporal sequence of propagation through the heart. SA, sino-atrial; AV, atrio-ventricular; RV, right ventricle; LV, left ventricle.

Figure 2. Structure, expression and assembly of voltage-gated K⁺ channel pore-forming (α) and accessory (minK and β) subunits

A, Kv α subunits are integral membrane proteins with six transmembrane domains, intracellular N- and C-termini and a positively charged S4 region, placing them in the ‘S4 superfamily’ of voltage-gated ion channels. B, schematic representation of outward K⁺ current waveforms produced on heterologous expression of a Kv α subunit of the Shal subfamily, Kv4.2, which gives rise to K⁺ currents that activate and inactivate rapidly on membrane depolarization. C, schematic diagram of a voltage-gated K⁺ channel illustrating the assembly of four Kv α subunits to produce a K⁺-selective pore. D, schematic diagram of functional voltage-gated cardiac K⁺ channels with Kv α subunits depicted in blue, cytosolic β (or KChAP) subunits in yellow and minK (or MiRP1) subunits in red.