Inwardly rectifying potassium channels: Introduction


The family of inwardly-rectifying potassium channels, i.e., Kir channels, plays central roles in control of cellular excitability and K+ ion homeostasis. Kir channels function in many tissues, including brain, heart, kidney, endocrine and sensory. Kir channels are structurally distinct from the family of voltage-gated potassium channels; Kir 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, Kir 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 Kir family have been identified in mammals. This article presents the molecular relationships and physiological roles of Kir channels and provides an introduction to their molecular, structural, physiological, and pharmacological properties.

Kir channel subunits, classification and nomenclature

Several key studies in the 1970's led to the description of two distinguishing properties of Kir channels, (i) inward rectification and (ii) the presence of a "long" pore (Hille, 2001). Kir 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 Kir conductance depends on the extracellular potassium concentration (Hille, 2001). Following cloning of the genes encoding Kir channel subunits (Dascal et al., 1993; Ho et al., 1993; Kubo et al., 1993a; Kubo et al., 1993b), 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 (Lopatin et al., 1994). 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 Kir 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 (EK), enabling Kir 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 Kir channels to the total potassium efflux. Thus, strongly rectifying Kir 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 KATP channel, which is gated by adenosine triphosphate (ATP). When KATP 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. Kir channels. A, Current-voltage relationship shows the property of inward rectification. Cells with a membrane potential that is positive to EK will conduct outward potassium current through Kir 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+ (Kv) channels and inwardly-rectifying K+ (Kir) channels. Both channels are tetramers and share an ion selectivity pore region (p-loop) and two transmembrane domains. Kv channels also have a voltage-sensitive domain (S4, red). C, All seven members of the Kir channels consist of a single alpha subunit that forms a tetramer. Kir6 channels uniquely require an additional subunit, the sulfonylurea receptor (SUR), to form a functional octameric channel.

A second distinguishing structural property of Kir 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 (Hagiwara and Takahashi, 1974). This property can be explained by the presence of a multi-ion, single-file pore (Hille, 2001). Recent structural determinations of Kir channels have revealed the physical nature of the long pore (see below).

A phylogenic tree representation based on amino acid sequence alignments of the Kir genes (Fig. 2) illustrates the relationships between the seven structural Kir subfamilies. Interestingly, members of each subfamily exhibit distinct functional properties as a consequence of their structural differences. Kir1 channels, found primarily in kidney cells, are regulated by pH and protein kinases. Kir2 channels are expressed in neuronal and non-neuronal cells, and are constitutively active. Kir3 channels are activated by G proteins, alcohol and sodium ions. Strongly pH-sensitive Kir4/Kir5 channels are prominent in astrocytes. Kir6 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 Kir channels. Amino acid sequence alignments for 15 known members of the human Kir family were created using CLUSTALV.

Structurally, all Kir 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 Kir channels appear to form as alpha subunit homotetramers, or heterotetramers of related sub-family members, without need of any obligate beta subunits (Fig. 1C). Kir6 members, on the other hand, must coassemble with SUR to form an octameric channel, with four Kir6 subunits forming the pore and four SUR subunits surrounding the Kir6 subunits (Shyng and Nichols, 1997; Zerangue et al., 1999). Kir channel sub-families generally associate with subunits from only the same subfamily. For example, Kir3.1 assembles with Kir3.2 but not with Kir2.1. A few exceptions to this rule have been reported, however, e.g., Kir4/Kir5 & Kir2.2/Kir4 (Fakler et al., 1996; Pessia et al., 1996).

In the late 1990s, a third key property for all Kir 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 Kir channels, indicating that PIP2 is an essential co-factor for Kir channel function (Huang et al., 1998). Some gating modifiers, such as G proteins and ATP, appear to alter the interaction with PIP2, thereby changing the level of channel activity (Baukrowitz et al., 1998; Huang et al., 1998; Shyng and Nichols, 1998). In addition, activation of Gq-coupled GPCRs can reduce Kir currents by temporarily depleting PIP2 (Kobrinsky et al., 2000). Stimulation of GPCRs that couple to Gq 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 Kir channels thus far, require the membrane phospholipid, PIP2, for activity (Hilgemann et al., 2001).

Kir interacting proteins

To date, a small handful of Kir-interacting proteins have been identified. Kir1.1 channels interact with Na+/H+ exchange regulatory factor 2 in the postsynaptic density 95/disc-large/zona occludens (PDZ) complex (Yoo et al., 2004). The Kir2 family of channels contains a class I PDZ binding motif and associates directly with synapse-associated protein 97 (SAP97) and PSD95 (Nehring et al., 2000; Inanobe et al., 2002). Calmodulin-dependent serine protein kinase (CASK), Veli, and Mint1 have also been shown to influence Kir2 trafficking (Leonoudakis et al., 2004a; Leonoudakis et al., 2004b). Kir3.2c and Kir3.3 subunits contain a class I PDZ binding motif that binds directly to the PDZ domain of sorting nexin 27 (SNX27) (Lunn et al., 2007; Balana et al., 2011). Interestingly, the PDZ binding motif of Kir3.2c/Kir3.3 does not bind to the PDZ domain of PSD95, due to specific amino acids upstream from the motif (Balana et al., 2011). Kir4.1 in glial cells and Kir2.2 in muscle associate with the dystrophin-glycoprotein complex via α-syntrophin (Connors et al., 2004). KATP channel complexes have been found to associate with multiple additional proteins, especially glycolytic enzymes (Hong et al., 2011), potentially through the SUR subunits.

Kir structures at atomic resolution

In 1998, the first atomic resolution structure of a bacterial potassium channel, Kcsa, was solved using X-ray crystallography (Doyle et al., 1998). 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 Kir channels in different states. Initially, structures were solved for the large intracellular cytoplasmic domains (CTD) of vertebrate Kir channels. To do this, the N-terminus was fused directly to the C-terminal domain, bypassing the membrane-spanning domains (Nishida and MacKinnon, 2002; Pegan et al., 2005; Inanobe et al., 2007) (Fig. 3). Based on the structures of the CTDs, it was proposed that Kir 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 (Pegan et al., 2005).

Subsequently full-length structures of Kir2.2 and Kir3.2 channels were solved, providing new insight to the mechanisms of PIP2-dependent gating, sodium-dependent gating, and G protein-dependent gating (Tao et al., 2009; Hansen et al., 2011; Whorton and MacKinnon, 2011). Most recently, a high-resolution structure of Gβγ-Kir3.2 was described (Whorton and MacKinnon, 2013), 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 (Nishida and MacKinnon, 2002; Pegan et al., 2005; Pegan et al., 2006; Inanobe et al., 2007; Aryal et al., 2009; Tao et al., 2009; Hansen et al., 2011; Whorton and MacKinnon, 2011, 2013). The determination of atomic resolution structures has significantly improved our understanding of Kir channel gating and function, but at the same time, raised new questions on Kir function. Thus, more atomic resolution structures of vertebrate Kir channels are anticipated in the future.

Figure 3. High resolution crystal structures of Kir channels. Kir3.1 (PDB:1N9P), Kir3.2 (PDB:2E4F), Kir2.1 (PDB:1U4F), Kir2.2 in the presence of PIP2 (PDB:3SPI) and Kir3.2 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 (Nishida and MacKinnon, 2002; Pegan et al., 2005; Pegan et al., 2006; Inanobe et al., 2007; Tao et al., 2009; Hansen et al., 2011; Whorton and MacKinnon, 2011, 2013).

Kir channels in disease

Numerous studies of mice expressing Kir mutant channels have been described that elucidate the function of particular Kir channel subunits in different tissues, and multiple human diseases have now been linked to point mutations in Kir genes tissues (for review, see Abraham et al (1999).

Mutations in Kir1 channels underlie Bartter syndrome, antenatal, type 2 (Simon et al., 1996). Loss of function mutations in Kir2.1 cause Andersen-Tawil syndrome (ATS), a rare multisystem disorder characterized by a long QT interval and ventricular arrhythmias, periodic paralysis and dysmorphic features (Plaster et al., 2001). In contrast, gain of function Kir2.1 mutations underlie short QT and predisposition to ventricular arrhythmias (Ambrosini et al., 2014). A recent genome-wide associative study (GWAS) study of alcoholics found single nucleotide polymorphisms (SNPs) in Kir3.2 (KCNJ6) (Kang et al., 2012), though it remains to be determined what impact the SNPs have on Kir3.2 function.

Kir4.1 has been associated with epilepsy in both causative and protective roles (Buono et al., 2004; Ferraro et al., 2004), including a role in the monogenic SESAME/EAST syndromes (Scholl et al., 2009; Reichold et al., 2010; Sala-Rabanal et al., 2010). Loss of Kir4.1 expression abolishes endocochlear potential and causes deafness in Pendred syndrome (Wangemann et al., 2004).

Disruption of the Kir6.1 gene in mice was reported to cause phenotypes similar to those of vasospastic (Prinzmetal) angina (Miki et al., 2002), and loss of function mutations in Kir6.2 cause human hyperinsulinism (Nichols et al., 1996). Conversely, activating mutations in Kir6.2 cause permanent neonatal diabetes (Gloyn et al., 2004) and are linked to type 2 diabetes (Hani et al., 1998; Gloyn et al., 2003; Villareal et al., 2009). In humans, gain-of-function mutations in Kir6.1 have now been associated with Cantu syndrome, a complex disease mimicking effects of potassium channel opener overdose (Brownstein et al., 2013; Cooper et al., 2014).

For additional information on different Kir channels and more comprehensive list of citations, please consider some of these more extensive reviews (Nichols and Lopatin, 1997; Hibino et al., 2010; Lüscher and Slesinger, 2010)


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