Introduction

Since the initial cDNA cloning of the first inward rectifiers K_ir1.1 (ROMK1) and K_ir2.1 (IRK1) in 1993, a succession of new members of this family have been identified, including the G protein-coupled K_ir3 and the ATP-sensitive K_ir6. These channels play an important physiological role in the function of many organs, including brain, heart, kidney, endocrine cells, ears, and retina. The phylogenic tree shown in Fig. 1 illustrates the relationships between the seven K_ir subfamilies based on amino acid sequence alignments. No new members of this family have been identified since this tree appeared in the 2002 edition of The IUPHAR Compendium of Voltage-Gated Ion Channels, and it is unlikely that any other members remain to be discovered.

In the K_ir section of the 2002 edition, we cited a very limited number of original cDNA cloning papers (Kubo et al., 2002). The scope of these citations has been expanded herein so that inferences on the molecular architecture and functional and pharmacological aspects can be readily drawn. Some of the newer work cited in this article is outlined below. It is noteworthy that much of this work describes the identification of associating proteins and the link between particular K_ir genes and human diseases. These kinds of findings are expected to continue to increase:

1. The interaction of K_ir1.1 with Na⁺/H⁺ exchange regulatory factor 2 in the postsynaptic density 95/disc-large/zona occludens (PDZ) complex was reported (Yoo et al., 2004).

2. The assembly of K_ir2.1 channels with synapse-associated protein 97 (SAP97), calmodulin-dependent serine protein kinase (CASK), Veli, and Mint1 and their contribution to protein trafficking was shown (Leonoudakis et al., 2004).

3. K_ir4.1 in glial cells and K_ir2.2 in muscle were shown to associate with the dystrophin-glycoprotein complex via α-syntrophin (Connors et al., 2004).

4. K_ir4.1 has been associated with epilepsy in both causative and protective roles (Buono et al., 2004; Ferraro et al., 2004; Leonoudakis et al., 2004).

5. It was shown that the loss of K_ir 4.1 expression abolishes endocochlear potential and causes deafness in Pendred syndrome (Wangemann et al., 2004).

6. The disruption of K_ir6.1 gene in mice was reported to cause phenotypes similar to those of vasospastic (Prinzmetal) angina (Miki et al., 2002).

7. It was shown that an activating mutation of K_ir6.2 causes permanent neonatal diabetes (Gloyn et al., 2004).

Although it is not discussed herein, among the most exciting recent developments are those involving X-ray crystal structure analysis, including studies describing the structure of the cytoplasmic region of K_ir3.1 (Nishida and MacKinnon, 2002), the entire structure of the bacterial K_ir1.1 channel (Kuo et al., 2003), and the cytoplasmic region of K_ir2.1 (Pegan et al., 2005). These studies demonstrated that inward rectifier K⁺ channels have a long cytoplasmic pore and confirmed the significance of negatively charged amino acids on the wall of the cytoplasmic pore that have been known to play critical roles for inward rectification. They also provided structure-based clues for the regulation mechanisms of gating by ligands such as G proteins and phosphatidylinositol 4,5-bisphosphate. The information yielded by analysis of crystal structures is extremely valuable since it will enable more precise approaches to establishing structure-function relationships. Also noteworthy are published studies on the dynamic aspects of channel function using fluorescence resonance energy transfer analysis of fluorescent-labeled molecules (Riven et al., 2003). Knowledge of these dynamic aspects of K_ir channel function may also be expected to expand in the near future.

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Fig. 1.

Phylogenetic tree of K_ir channels. Amino acid sequence alignments and phylogenetic analysis for the 15 known members of the human K_ir family were generated as described in the legend for Fig. 1 of “LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassiuim Channels”. No new channels have been added to this topology since it appeared in the earlier edition of this compendium. International Union of Pharmacology and HUGO Gene Nomenclature Committee names of the genes are shown together with their chromosomal localization.

A great deal of additional knowledge on K_ir function, structure-function relationships, regulation of expression, and links with diseases has been accumulated. Since it is not possible to describe it in detail here, we refer the reader instead to several excellent recent reviews (Stanfield et al., 2002; Bichet et al., 2003; Lu, 2004). See Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 for K_ir1 through K_ir7.1.