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I. INTRODUCTION

The domain is composed of outer TM1 and inner TM2 membrane spanning helices, with two short additional helical elements, the slide and the pore helices. The channel pore is delimited by one TM2 helix from each of the four Kir subunits. The ion conduction pore Fig. This makes a narrow region in the ion conduction pathway which separates the central cavity from the extracellular solution.


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The bases of four TM2 helices one from each subunit come together to make another narrow region at the cytoplasmic face of the channel. There are two distinct gating mechanisms in Kir channels: slow gating and fast gating. In single-channel recordings, slow gating corresponds to channel openings occurring as bursts separated by long closed periods, and fast gating corresponds to rapid opening and closing within the burst.

Mutations introduced around the bundle crossing area of the inner TM2 helix tend to modulate the behavior of bursts , , On the other hand, mutations around the selectivity filter cause alterations in fast gating 85 , 87 , , , , Each TM2 helix can bend around a hinge point Gly about halfway along their length.

This bending would vary the cross-sectional area of the narrow region at the cytoplasmic face of the transmembrane domain. Jin et al. They also found that replacement of certain residues in the TM2 helix below G with Pro, which would increase the flexibility of the TM2 helix, formed constitutively active channels This idea is similar to the gating mechanism of the KcsA channel proposed by Jiang et al.

Finding Channels

In addition to the importance of Gly as a hinge, another residue in the TM2 helix seems to play a role in activation gating. In Kir3. The corresponding residue in KirBac1. Comparisons between Kir3. In the constitutively inactive channel Kir3. Homology modeling suggested that, in the closed state, V might mediate an interaction between adjacent TM2 helixes and the VG mutation destabilized the closed conformation by disrupting this interaction The corresponding residue I in the constitutively active Kir2.

These structural differences imply that, in Kir3. This model is also supported by the following observation. Homology modeling of Kir1. Further analyses of Kir1. While the pore lining helices in the KcsA structure are arranged in a fourfold symmetry, those in KirBac1. This is quite different from the character of the selectivity filter of KcsA and KirBac3.

Distribution and function of voltage-gated sodium channels in the nervous system

These structural alterations around the selectivity filter may also serve to gate Kir channels, and they may correspond to fast gating. Since the slide helix is amphiphilic, it may lie at the interface between the inner leaflet of membrane and the cytoplasm. Loss-of-function mutations in the slide helix of Kir1. Therefore, the slide helix has important roles to play in Kir channel function. The crystal structure of the cytoplasmic domains of Kir channels has been obtained in two ways. These results have proven to be comparable to the lesser resolution data obtained from entire Kir channels , Therefore, conformational information obtained from the cytoplasmic region of Kir channels should correspond to that of the overall structure of the entire channel protein.

But data concerning the region connecting NH 2 and COOH termini and the membrane interface should be interpreted with caution. It is worth noting that the amino acid sequence of regions connecting NH 2 and COOH termini to the membrane segment is conserved among the Kir channel family Fig. The cytoplasmic domain is mainly formed from the COOH terminus of each subunit, while the NH 2 termini are present between adjacent COOH termini and they contribute to formation of the interface between subunits.

This contributes to the stability of the whole cytoplasmic region. Huang et al. The detailed structure of the cytoplasmic pore and its relevance to channel function and channelopathies will be discussed in reference to Kir2. Although several residues responsible for this block have been identified on the inner TM2 helix in the transmembrane domain, others have been identified in the cytoplasmic domain , , , , , These acidic residues have been mapped to the wall of the pore of the cytoplasmic domain see sect.

In Kir channels, a number of basic and uncharged residues in the cytoplasmic region of the channel are proposed to be involved in the action of PtdIns 4,5 P 2 , , , , , , , , , , , These are mostly to be found upon the surface of the cytoplasmic region which faces the membrane Fig. Residues in the transmembrane region may also participate in the association between the channel and PtdIns 4,5 P 2 ; they include basic residues clustered in lower part of the inner TM2 helix and an uncharged residue in the slide helix , However, the mechanism of action of PtdIns 4,5 P 2 has not been fully elucidated.

The crystal structure of the KirBac3.

Ion channels (voltage gated, ligand gated, stress activated ion channel)

The cross-sectional area of the space surrounded by the HI loops is wide in Kir3. Mutations in the HI loop disrupted gating and affected inward rectification of Kir2. In the crystallization of the KirBac3. A prominent difference between the two is found in the apex of the cytoplasmic pore formed by the HI loop G-loop. In one conformation the apex is dilated, whereas in the other it is constricted. These two conformations of the chimera channel may represent open and closed states of the cytoplasmic pore, respectively.

In support of this idea, several loss-of-function mutations in Kir channelopathies are found in the residues forming the apex see sect. Structural analyses of Kir3. Biochemical assays show that, in Kir2.

The modulation of the conformation of NH 2 and COOH termini and their interaction clearly play pivotal roles in the regulation of Kir channel gating. Tetraethylammonium TEA and 4-aminopyridine 4-AP are known as the inhibitors of K v channels but have little effects on Kir channels , They inhibit Kir channels more strongly as the membrane is hyperpolarized , , , However, there are different aspects in the behavior of the two blockers.

In spite of a limited number of blockers of Kir channels see above , pharmacological and physiological assays have revealed other compounds that can affect particular types of Kir channels. Tertiapin is a toxin that was isolated from honey bee venom which blocks K G and Kir1. These reagents are also useful tools to examine basic properties of K ATP channels.

The channels of this family are constitutively active and exhibit strong inward rectification. They contribute to the establishment of highly negative E res and long-lasting action potential plateau in various cells including cardiac myocytes.

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Afterward, three more subunits were identified as members of this family. They are Kir2. The amino acid sequence of mouse brain Kir2. Initially Kir2. However, recent studies have revealed that Kir2.

PART I Voltage-Dependent Potassium Channels

Indeed, in vitro electrophysiological experiments have shown that each of Kir2. Some of these heteromers have been identified in native tissues. For example, heteromeric assemblies of Kir2. Table 1. Biophysical properties of Kir2. NE, not examined; XO, Xenopus oocytes. The basic architecture of Kir channels with transmembrane and cytoplasmic regions and pore structure see Fig. Studies of mutated Kir2. The strong rectifier Kir2. Another residue in the TM2 helix, S in Kir2. The crystal structure of KirBac1.

Further site-directed mutagenesis has identified negatively charged amino acids Glu at two different positions E and E for Kir2. Structural information from KirBac, Kir3. The reason why Kir2. It is possible that these two types of binding sites play distinct roles: polyamines may plug the pore in the transmembrane domain plugging site , whereas the cytoplasmic region would serve as an intermediate binding site nonplugging site that increases the local concentration of polyamines around the plugging site , , , Analysis of the crystal structure of the cytoplasmic domain of Kir2.

A is localized at the apex of the G-loop. Because the side chain of these residues is larger than that of Ala, these substitutions would result in the physical occlusion of the G-loop without changing its backbone conformation. When another constituent of the G-loop M was mutated to Ala, an enhancement of inward rectification was observed. Thus the G-loop also contributes to inward rectification in Kir2. The structure of the cytoplasmic pore region of Kir2. Side left and bottom right and top-down top right ; membrane to cytoplasm views of the cytoplasmic region NH 2 and COOH termini of the Kir2.

Other residues near the G-loop are labeled. This illustration was constructed from protein database ID 1U4F The sequence that was first found to be associated with activation of Kir2. In Kir2. Andersen syndrome is caused by dysfunction of Kir2. They generally disrupt Kir2. For example, V is located near the apex of the cytoplasmic structure. Table 2.


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Human Kir channelopathies. ND, not determined. As summarized in Table 1 , the channels made up of various homo- and heteromultimers of Kir2. The steady-state open probability P o of Kir2.