Molecular Regulation of Cardiac Inward Rectifier Potassium Channels

Introduction

Potassium channels play a critical role in modulating cardiac excitability via their effects on the resting membrane potential and on the action potential waveform. The potassium channel family is diverse and comprises the voltage-gated, inwardly rectifying (Kir), small-conductance calcium-activated, and two-pore domain K ⁺ channel subfamilies. The currents that flow through Kir channels include the inward rectifier (I _K1 ), the acetylcholine-activated (I _K(Ach) ), and the adenosine triphosphate (ATP)–sensitive (I _K(ATP) ) currents. The Kir α-subunit is composed of two transmembrane domains (M1 and M2), flanking a pore-forming motif that contains the signature glycine-tyrosine-glycine (GYG) sequence of the K ⁺ selectivity filter and intracellular N- and C-termini. The channels can homo- or heterotetramerize. Kir channels lack the voltage-gating behavior that depends on the presence of an S4 transmembrane voltage-sensing domain, which is typically present in voltage-gated channels. The pore-forming α-subunits are composed of Kir1.x to Kir7.x proteins, encoded by the KCNJ1 through KCNJ16 genes. In the cardiac myocyte, Kir2.x, Kir3.x, and Kir6.x are expressed ( Table 4.1 ); however, their expression profile is variable among animal species and among the different cardiac chambers. Kir channels are characterized by inward rectification, where the potassium current is better conducted in the inward direction. Rectification depends on the block of the outward K ⁺ flow by cytoplasmic divalent cations and positively charged polyamines. I _K1 and I _K(Ach) are considered strong rectifiers, whereas I _K(ATP) is a weak rectifier. This chapter focuses on the molecular regulation of the cardiac Kir channels in light of our structural biology–based understanding of their modulation by small molecules.

TABLE 4.1

Inward Rectifiers Expressed in the Mammalian Heart

Subfamily	Protein	Gene	Current
Kir2	Kir2.1	KCNJ2	I _K1
	Kir2.2	KCNJ12	I _K1
	Kir2.3	KCNJ4	I _K1
Kir3	Kir3.1	KCNJ3	I _K(Ach)
	Kir3.4	KCNJ5	I _K(Ach)
Kir6	Kir6.1	KCNJ8	I _K(ATP)
	Kir6.2	KCNJ11	I _K(ATP)

Inward Rectifier Potassium Current

Molecular Basis

In cardiac myocytes, Kir channels are encoded by a diverse subfamily of α-subunit genes (see Table 4.1 ). Several members of the Kir2.x subfamily (Kir2.1 to Kir2.3) are expressed in the myocardium, and it has been shown that Kir2.1 can homo- or heterotetramerize with Kir2.2 and Kir2.3 to conduct cardiac I _K1 , depending on the species and the cardiac chamber. Early crystallographic data have shown that the selectivity filter of Kir channels, and their bacterial homolog, contain a GYG potassium selectivity filter signature motif in the P loop region of the channel, located close to the extracellular side of the membrane, followed by a water cavity, after which the pore narrows toward the intracellular side of the membrane. ^, In the cytoplasmic domain, Kir channels progressively widen, forming an intracellular ion permeation pathway. Several studies have identified residues that are critical for regulating rectification. Residue D172 was recognized as a transmembrane “rectification controller” responsible for the “steep” (highly voltage-dependent) rectification. On the other hand, acidic residues in the cytoplasmic region of Kir2.1, such as E224 and E299, are involved in “shallow” (less voltage-dependent) rectification. ^, There is strong evidence that polyamines (e.g., spermine) bind with robust affinity in the vicinity of D172 and a selectivity filter, whereas E224, D259, and E299 provide low-affinity binding sites. ^, The proximal C-terminus and the M2 domain control the ability of Kir2.1 to interact with other Kir subunits, and several sites have been identified as crucial for interaction with modulators such as PIP2, with ions such as Na ⁺ , and with kinases such as protein kinase C (PKC) and protein kinase A (PKA). ^,

Physiology

In the cardiac myocyte, I _K1 contributes to phase 3 repolarization and plays a role in establishing the resting membrane potential. There are, however, marked regional differences in I _K1 expression in atria, ventricles, and the specialized conduction system and among species as well. For instance, I _K1 density is higher in ventricular myocytes, including Purkinje myocytes, compared with the atria. Furthermore, I _K1 density is small in sinoatrial (SA) nodal pacemaker cells of mice and rats and almost undetectable in the sinoatrial node (SAN) and atrioventricular node (AVN) of larger animals. There are also ventricular chamber–specific differences in I _K1 density, but the density seems to be similar in epicardial, M, and endocardial cells in canine and guinea pig hearts. Kir2.1 channels are thought to be abundantly expressed in the T-tubular membrane. ^, ^,

Pathophysiology

Because Kir channels are involved in maintaining the resting membrane potential and K ⁺ transport across the membrane, they are associated with many vital physiologic functions, where their aberrant malfunctioning can cause several systemic diseases ranging from cardiovascular and neurologic disorders to renal dysfunction and neonatal diabetes. Loss-of-function or gain-of-function mutations in Kir2.1 have been identiﬁed in long QT syndrome 7 (LQT7), also known as Andersen-Tawil syndrome, an inherited channelopathy that leads to QT prolongation, U wave prominence, and ventricular arrhythmias, including bidirectional ventricular tachycardia. ^, Some LQT7-causing mutations affect phosphatidylinositol 4,5-bisphosphate (PIP2) binding to Kir2.1, whereas other mutations result in a trafficking defective Kir2.1 and channel loss of function. Some cases of short QT syndrome, congenital atrial fibrillation (AF), and catecholaminergic polymorphic ventricular tachycardia (CPVT) have been attributed to gain-of-function mutations in Kir2.1. Furthermore, changes in the density and biophysical properties of I _K1 have been observed in pathophysiology. For instance, I _K1 is downregulated in patients with severe heart failure and cardiomyopathies. ^, Reduced I _K1 density was observed in subendocardial Purkinje myocytes from the infarcted dog heart and in endocardial, epicardial, and M cells of failing canine hearts. Loss of I _K1 is thought to produce membrane depolarization, prolongation of the action potential duration (APD), and both early and delayed afterdepolarizations. ^, On the other hand, I _K1 density is increased in experimental models and in patients with chronic AF. ^, Moreover, a tachypaced sheep model of AF showed that the rate of acceleration and stabilization of the fibrillatory activity during transition from paroxysmal to persistent AF was reflected by changes in APD and densities of ionic currents, including the upregulation of I _K1 and Kir2.3 protein.

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