Cardiac strong inward rectifier potassium channels

Abstract

Cardiac I(K1) and I(KACh) are the major potassium currents displaying classical strong inward rectification, a unique property that is critical for their roles in cardiac excitability. In the last 15 years, research on I(K1) and I(KACh) has been propelled by the cloning of the underlying inwardly rectifying potassium (Kir) channels, the discovery of the molecular mechanism of strong rectification and the linking of a number of disorders of cardiac excitability to defects in genes encoding Kir channels. Disease-causing mutations in Kir genes have been shown experimentally to affect one or more of the following channel properties: structure, assembly, trafficking, and regulation, with the ultimate effect of a gain- or a loss-of-function of the channel. It is now established that I(K1) and I(KACh) channels are heterotetramers of Kir2 and Kir3 subunits, respectively. Each homomeric Kir channel has distinct biophysical and regulatory properties, and individual Kir subunits often display different patterns of regional, cellular, and membrane distribution. These differences are thought to underlie important variations in the physiological properties of I(K1) and I(KACh). It has become increasingly clear that the contribution of I(K1) and I(KACh) channels to cardiac electrical activity goes beyond their long recognized role in the stabilization of resting membrane potential and shaping the late phase of action potential repolarization in individual myocytes but extends to being critical elements determining the overall electrical stability of the heart.

Figure 1. The family of inward rectifier potassium channels

All members of this family share significant structural similarity but only Kir2 and Kir3 subfamilies represent channels carrying classical strongly rectifying currents. Four members of each Kir2 and Kir3 subfamilies were cloned in mammals. Heteromeric assemblies of Kir2.1, Kir2.2 and Kir2.3 subunits underlie I_K1 current, and heteromeric assembly of Kir3.1 and Kir3.4 subunits underlies I_KACh current. Other nomenclatures of Kir channels can be found in IUPHAR database (http://www.iuphar-db.org), and in the ‘International Union of Pharmacology. LIV’[13].

Figure 2. Essential properties of classical inward rectification

(A) The pore of a prototypic inward rectifier channel consists of long tunnel extending far inside the cell. A ‘ring’ of negatively charged residues at the level of intra-membrane water cavity (D172 in Kir2.1) is critical for high-affinity strongly-voltage dependent block of Kir channels by intracellular polyamines (e.g. spermine). Another ring of negatively charged residues (including but not limited to E224 and E299 in Kir2.1) is essential for a low-affinity weak-voltage-dependent block by polyamines. (B) Block of the Kir channel pore by intracellular polyamines and Mg²⁺ ions in response to membrane depolarization leads to a voltage-dependent decline of K⁺ conductance producing a region of ‘negative slope’ conductance. Increase in the concentration of extracellular K⁺ leads to a near parallel shift of current/voltage relationships and their ‘crossover’. (C) Rectification profiles are distinct in different Kir channels. When current amplitudes are normalized at far negative membrane potentials the outward currents are the smallest for Kir2.2 and the largest for Kir3.1/Kir3.4 channels.

Figure 3. Mutations on Kir2.1 protein associated with channelopathies of the classical inward rectifier channel

Mutant residues are color coded to represent the Long QT7 (LQT7; black), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT; red), Familial Atrial Fibrillation (FAF; green) and Short QT3 (SQT3; blue).