Introduction

The family of inwardly-rectifying potassium channels, i.e., K_ir channels, plays central roles in control of cellular excitability and K⁺ ion homeostasis. K_ir channels function in many tissues, including brain, heart, kidney, endocrine and sensory. K_ir channels are structurally distinct from the family of voltage-gated potassium channels; K_ir channels possess only two membrane-spanning helices, and lack the four membrane helices that form the voltage sensor in voltage-gated potassium channels. As such, K_ir channels have evolved distinct voltage-independent mechanisms for opening and closing, including gating by G proteins, pH and ATP. Seven structurally distinct sub-families of the K_ir family have been identified in mammals. This article presents the molecular relationships and physiological roles of K_ir channels and provides an introduction to their molecular, structural, physiological, and pharmacological properties.

K_ir channel subunits, classification and nomenclature

Several key studies in the 1970's led to the description of two distinguishing properties of K_ir channels, (i) inward rectification and (ii) the presence of a "long" pore [21]. K_ir channels derive their name, i.e., inwardly-rectifying, from the current-voltage relationship. When the current through the channel is plotted as a function of membrane potential, the inward current, i.e., negative current, is typically much larger than the positive ('outward') current (Fig. 1A). This property is referred to as inward rectification (or 'anomalous' rectification), to distinguish it from the classical 'outward' rectification expected of a passive pore in the presence of high internal and low external potassium. Increasing the concentration of extracellular potassium shifts the peak of the outward current to more depolarized potentials (Fig. 1A), such that the voltage-dependence of the K_ir conductance depends on the extracellular potassium concentration [21]. Following cloning of the genes encoding K_ir channel subunits [10,22,29-30], it was determined with heterologous expression systems, such as Xenopus oocytes or HEK-293 cells, that rectification is not an intrinsic property of the channel protein [33]. Rather, intracellular factors, e.g., Mg²⁺ and polyamines, bind to the inner ion-conducting vestibule of the channel, where they impede the outward flow of potassium ions.

The extent of inward rectification also appeared to vary in different types of cells, leading to further classification of K_ir channels into two major groups, 'weak' and 'strong' inward rectifiers. The biological significance of strong inward rectification is perhaps best seen in excitable cells, such as cardiac and neuronal cells. Here, the resting membrane potential of these cells is typically slightly positive to the equilibrium potential for potassium (E_K), enabling K_ir channels to sustain a small amount of potassium efflux (Figure 1A). As the cell depolarizes, such as during an action potential, the property of rectification limits the contribution of K_ir channels to the total potassium efflux. Thus, strongly rectifying K_ir channels play an important role in controlling the resting potential and excitability, but contribute little to the action potential itself. In contrast, weak inward rectifiers will both stabilize the resting potential and shorten the action potential. A good example is the so-called K_ATP channel, which is gated by adenosine triphosphate (ATP). When K_ATP channels are activated in the heart, they can reduce the classically long action potential from a duration of hundreds of milliseconds to that of a brief spike.

Figure 1. K_ir channels. A, Current-voltage relationship shows the property of inward rectification. Cells with a membrane potential that is positive to E_K will conduct outward potassium current through K_ir channels, which will decline substantially at more positive potentials. The apparent gating of the channel shifts with increasing extracellular K⁺ concentration. B, Schematic compares the membrane topology of voltage-gated K⁺ (K_v) channels and inwardly-rectifying K⁺ (K_ir) channels. Both channels are tetramers and share an ion selectivity pore region (p-loop) and two transmembrane domains. K_v channels also have a voltage-sensitive domain (S4, red). C, All seven members of the K_ir channels consist of a single alpha subunit that forms a tetramer. K_ir6 channels uniquely require an additional subunit, the sulfonylurea receptor (SUR), to form a functional octameric channel.

A second distinguishing structural property of K_ir channels is the presence of an extended pore that continues from the transmembrane regions through the cytoplasmic domain. The conductance of inward rectifiers depends on the square root of the external potassium concentration [16]. This property can be explained by the presence of a multi-ion, single-file pore [21]. Recent structural determinations of K_ir channels have revealed the physical nature of the long pore (see below).

A phylogenic tree representation based on amino acid sequence alignments of the K_ir genes (Fig. 2) illustrates the relationships between the seven structural K_ir subfamilies. Interestingly, members of each subfamily exhibit distinct functional properties as a consequence of their structural differences. K_ir1 channels, found primarily in kidney cells, are regulated by pH and protein kinases. K_ir2 channels are expressed in neuronal and non-neuronal cells, and are constitutively active. K_ir3 channels are activated by G proteins, alcohol and sodium ions. Strongly pH-sensitive K_ir4/K_ir5 channels are prominent in astrocytes. K_ir6 channels coassemble with an accessory subunit, sulfonylurea receptor (SUR), to form the ATP-sensitive channels that are inhibited by ATP.

Figure 2. Phylogenetic tree for K_ir channels. Amino acid sequence alignments for 15 known members of the human K_ir family were created using CLUSTALV.

Structurally, all K_ir channels have two membrane-spanning domains, a p-loop that forms the ion selectivity filter, and intracellular N- and C-terminal domains (Fig. 1B). Most K_ir channels appear to form as alpha subunit homotetramers, or heterotetramers of related sub-family members, without need of any obligate beta subunits (Fig. 1C). K_ir6 members, on the other hand, must coassemble with SUR to form an octameric channel, with four K_ir6 subunits forming the pore and four SUR subunits surrounding the K_ir6 subunits [48,57]. K_ir channel sub-families generally associate with subunits from only the same subfamily. For example, K_ir3.1 assembles with K_ir3.2 but not with K_ir2.1. A few exceptions to this rule have been reported, however, e.g., K_ir4/K_ir5 & K_ir2.2/K_ir4 [12,43].

In the late 1990s, a third key property for all K_ir channels was discovered. The plasma membrane contains a high concentration of a particular type of phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP₂). Depletion of PIP2 reduces the activity of K_ir channels, indicating that PIP₂ is an essential co-factor for K_ir channel function [24]. Some gating modifiers, such as G proteins and ATP, appear to alter the interaction with PIP2, thereby changing the level of channel activity [5,24,49]. In addition, activation of G_q-coupled GPCRs can reduce K_ir currents by temporarily depleting PIP₂ [28]. Stimulation of GPCRs that couple to G_q G proteins leads to activation of phospholipase C (PLC), which generates inositol triphosphate (IP₃) and diacylglycerol (DAG) through hydrolysis of PIP₂, thereby temporarily reducing the effective concentration of PIP₂ within the membrane inner leaflet. All K_ir channels thus far, require the membrane phospholipid, PIP₂, for activity [20].

K_ir interacting proteins

To date, a small handful of K_ir-interacting proteins have been identified. K_ir1.1 channels interact with Na⁺/H⁺ exchange regulatory factor 2 in the postsynaptic density 95/disc-large/zona occludens (PDZ) complex [56]. The K_ir2 family of channels contains a class I PDZ binding motif and associates directly with synapse-associated protein 97 (SAP97) and PSD95 [25,37]. Calmodulin-dependent serine protein kinase (CASK), Veli, and Mint1 have also been shown to influence K_ir2 trafficking [31-32]. K_ir3.2c and K_ir3.3 subunits contain a class I PDZ binding motif that binds directly to the PDZ domain of sorting nexin 27 (SNX27) [4,34]. Interestingly, the PDZ binding motif of K_ir3.2c/K_ir3.3 does not bind to the PDZ domain of PSD95, due to specific amino acids upstream from the motif [4]. K_ir4.1 in glial cells and K_ir2.2 in muscle associate with the dystrophin-glycoprotein complex via α-syntrophin [8]. KATP channel complexes have been found to associate with multiple additional proteins, especially glycolytic enzymes [23], potentially through the SUR subunits.

K_ir structures at atomic resolution

In 1998, the first atomic resolution structure of a bacterial potassium channel, Kcsa, was solved using X-ray crystallography [11]. This landmark study began a revolution of new research, moving away from mutagenesis-electrophysiology experiments, i.e., so called 'structure-function' studies, to determining the high-resolution structures of K_ir channels in different states. Initially, structures were solved for the large intracellular cytoplasmic domains (CTD) of vertebrate K_ir channels. To do this, the N-terminus was fused directly to the C-terminal domain, bypassing the membrane-spanning domains [26,40,42] (Fig. 3). Based on the structures of the CTDs, it was proposed that K_ir channels contain two gates, a G loop gate in the CTD, and a bundle-crossing gate in the membrane-spanning domains; both of which would have to be open for the channel to conduct potassium ions [42].

Subsequently full-length structures of K_ir2.2 and K_ir3.2 channels were solved, providing new insight to the mechanisms of PIP₂-dependent gating, sodium-dependent gating, and G protein-dependent gating [18,51,54]. Most recently, a high-resolution structure of Gβγ-K_ir3.2 was described [55], setting the stage for new structures of channels complexed with regulator proteins. Collectively, these structural studies demonstrated that inward rectifier K⁺ channels have a long cytoplasmic pore lined with negatively charged amino acids that are important for inward rectification. These studies also provided insights into the structural basis for gating by ligands such as G protein Gβγ subunits, sodium ions, ethanol, and PIP₂ [3,18,26,40-42,51,54-55]. The determination of atomic resolution structures has significantly improved our understanding of K_ir channel gating and function, but at the same time, raised new questions on K_ir function. Thus, more atomic resolution structures of vertebrate K_ir channels are anticipated in the future.

Figure 3. High resolution crystal structures of K_ir channels. K_ir3.1 (PDB:1N9P), K_ir3.2 (PDB:2E4F), K_ir2.1 (PDB:1U4F), K_ir2.2 in the presence of PIP₂ (PDB:3SPI) and K_ir3.2 with Gβγ in the presence of PIP₂ (PDB:4KFM). Highlighted regions include cytoplasmic domain (CTD), transmembrane domain (TMD), two 'gates', e.g. G-loop and bundle-crossing, PIP₂ and Gβγ subunits. Modified from [18,26,40-42,51,54-55].

K_ir channels in disease

Numerous studies of mice expressing K_ir mutant channels have been described that elucidate the function of particular K_ir channel subunits in different tissues, and multiple human diseases have now been linked to point mutations in K_ir genes tissues (for review, see [1]).

Mutations in K_ir1 channels underlie Bartter syndrome, antenatal, type 2 [50]. Loss of function mutations in K_ir2.1 cause Andersen-Tawil syndrome (ATS), a rare multisystem disorder characterized by a long QT interval and ventricular arrhythmias, periodic paralysis and dysmorphic features [44]. In contrast, gain of function K_ir2.1 mutations underlie short QT and predisposition to ventricular arrhythmias [2]. A recent genome-wide associative study (GWAS) study of alcoholics found single nucleotide polymorphisms (SNPs) in K_ir3.2 (KCNJ6) [27], though it remains to be determined what impact the SNPs have on K_ir3.2 function.

K_ir4.1 has been associated with epilepsy in both causative and protective roles [7,13], including a role in the monogenic SESAME/EAST syndromes [45-47]. Loss of K_ir4.1 expression abolishes endocochlear potential and causes deafness in Pendred syndrome [53].

Disruption of the K_ir6.1 gene in mice was reported to cause phenotypes similar to those of vasospastic (Prinzmetal) angina [36], and loss of function mutations in K_ir6.2 cause human hyperinsulinism [39]. Conversely, activating mutations in K_ir6.2 cause permanent neonatal diabetes [14] and are linked to type 2 diabetes [15,17,52]. In humans, gain-of-function mutations in K_ir6.1 have now been associated with Cantu syndrome, a complex disease mimicking effects of potassium channel opener overdose [6,9].

For additional information on different K_ir channels and more comprehensive list of citations, please consider some of these more extensive reviews [19,35,38].

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