Molecular Basis of Ion Selectivity, Block, and Rectification of the Inward Rectifier Kir3.1/Kir3.4 K+ Channel

Dibb, Katharine M.; Rose, Thierry; Makary, Samy; Claydon, Tom W.; Enkvetchakul, Decha; Leach, Robert; Nichols, Colin G.; Boyett, Mark R.

doi:10.1074/jbc.m307723200

Cited by 63 publications

(100 citation statements)

References 34 publications

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“…The effect of charge mutations on the block and rectification of Kir channels is well known (22)(23)(24)(25)(26)(27)(28)(29). We see a correlation between loss of K ϩ selectivity and reduced potency for channel block at depolarized potentials by intracellular Mg 2ϩ and polyamines, as previously reported (26,(30)(31)(32). However, the reduction of rectification by S177W is not as acute as what has been previously reported for other mutations, leading us to believe that the selectivity filter remains largely intact.…”

Section: Effect Of the M2 Helix Mutations On The Geometry Of The Selesupporting

confidence: 78%

“…Subsequent mutations were generated from this original WT model. It is of note that KirBac1.1 lacks two conserved residues that f lank the selectivity filter and play a crucial role in selectivity and function, possibly through forming a stabilizing salt bridge (31,38). This salt bridge was introduced at the initial stage of construction by using artificial restraints.…”

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confidence: 99%

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Electrostatic interactions in the channel cavity as an important determinant of potassium channel selectivity

Bichet

Grabe

Jan

2006

Proc. Natl. Acad. Sci. U.S.A.

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Potassium channels are membrane proteins that allow the passage of potassium ions at near diffusion rates while severely limiting the flux of the slightly smaller sodium ions. Although studies thus far have focused on the narrowest part of the channel, known as the selectivity filter, channels are long pores with multiple ions that traverse the selectivity filter, the water-filled central cavity, and the rest of the pore formed by cytoplasmic domains. Here, we present experimental analyses on Kir3.2 (GIRK2), a G proteinactivated inwardly rectifying potassium (Kir) channel, showing that a negative charge introduced at a pore-facing position in the cavity (N184) below the selectivity filter restores both K ؉ selectivity and inward rectification properties to the nonselective S177W mutant channel. Molecular modeling demonstrates that the negative residue has no effect on the geometry of the selectivity filter, suggesting that it has a local effect on the cavity ion. Moreover, restoration of selectivity does not depend on the exact location of the charge in the central cavity as long as this residue faces the pore, where it is in close contact with permeant ions. Our results indicate that interactions between permeant ions and the channel cavity can influence ion selectivity and channel block by means of an electrostatic effect.inward rectification ͉ permeation ͉ permeability ͉ GIRK modeling ͉ Kir3 P otassium channels are found in all kingdoms and domains and serve a wide range of important physiological functions, such as volume regulation and potassium transport in plants (1, 2) and the control of insulin release, blood flow, heart rate, neuronal signaling, and potassium secretion in the kidney and inner ear of animals (3-5). These physiological functions rely critically on the channel's ability to permeate K ϩ and not Na ϩ , which is smaller and more abundant in nature. To understand how K ϩ channels fulfill their physiological functions, and to gain some appreciation as to how their remarkable selectivity for K ϩ permeation might have evolved, it is important to characterize all of the features of the K ϩ channel pore that contribute to its ability to discriminate between potassium and other ions.Our understanding of K ϩ channel selectivity has gained considerable insight from the KcsA potassium channel crystal structure, which revealed that four identical subunits come together to form a central pore (6). The pore is most constricted over a narrow span, termed the selectivity filter, which is formed by four loops bearing the amino acid sequence GYG near the extracellular side of the membrane. This sequence is highly conserved throughout the K ϩ channel superfamily and is thought to underlie the basis of K ϩ selectivity; therefore, it is called the K ϩ channel signature sequence (7). Although it is clear that this sequence plays a key role in selectivity, it makes up only a fraction of the channel's entire permeation pathway, and the relative contributions to K ϩ selectivity from the selectivity filter and the r...

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Section: Effect Of the M2 Helix Mutations On The Geometry Of The Selesupporting

confidence: 78%

mentioning

confidence: 99%

Electrostatic interactions in the channel cavity as an important determinant of potassium channel selectivity

Bichet

Grabe

Jan

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…These salt bridges are thought to be important in sterically constraining the size of the inner mouth of the filter and, hence, controlling cation selectivity. 22 The remaining arginine substitution (L168R) may also disrupt salt bridge formation by introducing a local positive charge. It remains to be proven, but it seems plausible that these mutations would constitutively depolarize the cells within an APA.…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutations Affecting the Selectivity Filter of KCNJ5 Are Frequent in 2 Large Unselected Collections of Adrenal Aldosteronomas

et al. 2012

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Abstract-Primary hyperaldosteronism, one cause of which is aldosterone-producing adenomas (APAs), may account for Յ5% to 10% of cases of essential hypertension. Germline mutations have been identified in 2 rare familial forms of primary hyperaldosteronism, but it has been reported recently that somatic mutations of the KCNJ5 gene, which encodes a potassium channel, are present in some sporadic nonsyndromic APAs. To address this further we screened 2 large collections of sporadic APAs from the United Kingdom and Australia (totalling 73) and found somatic mutations in the selectivity filter of KCNJ5 in 41% (95% CI: 31% to 53%) of the APAs (30 of 73). These included the previously noted nonsynonymous mutations, G151R and L158R, and an unreported 3-base deletion, delI157, in the region of the selectivity filter. APAs containing a somatic KCNJ5 mutation were significantly larger than those without ( Key Words: hyperaldosteronism Ⅲ hypertension Ⅲ potassium channels Ⅲ KCNJ5 Ⅲ aldosterone-producing adenoma Ⅲ posture response P rimary hyperaldosteronism (PA) is now recognized as a common, treatable, and potentially curable form of hypertension, which may account for Յ10% of cases of socalled essential hypertension. [1][2][3] Most cases of PA are sporadic and result from 2 major types of adrenal pathology, an aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. In recently published series, the frequency of APA varied between 28% and 50% of patients with PA. 4 Choi et al 5 recently reported somatic mutations in a potassium channel, KCNJ5 (also called GIRK4 or Kir3.4), in 8 of 20 APAs studied and a germline mutation in the same gene in all 3 affected members of a family with florid, early onset, nondexamethasone-suppressible PA associated with marked hyperplasia of zona fasciculata (ZF), suggesting a novel pathway that might activate growth of aldosteronesecreting cells. These mutations within the selectivity filter of the potassium channel reduce the normal K ϩ /Na ϩ selectivity of the channel, and the resulting depolarization of the adrenocortical cell could lead to calcium loading and growth. However, the APAs carrying KCNJ5 mutations were large (mean of 2.8 cm and all Ͼ2 cm in diameter) and might represent a subgroup with a phenotype more relevant to the giant hyperplastic adrenals seen in the family with the germline KCNJ5 mutation. 5 To address this issue we have screened a large collection of APAs (totalling 73) from geographically distinct centers (United Kingdom and Australia) to determine whether somatic mutations of KCNJ5 are present in unselected APAs regardless of size. We also

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“…This discrepancy is probably a result of the well recognized lesser sensitivity to blocking drugs of channels expressed in Xenopus laevis oocytes compared with mammalian cells (Weerapura et al, 2002). Nevertheless, the mechanisms of channel block in X. laevis oocytes are believed to be similar to those in other systems, and X. laevis oocytes are widely used as an expression system for the analysis of structural motifs for channel block (Dibb et al, 2003;Wang et al, 2003;Decher et al, 2004;Perry et al, 2004).…”

Section: Herrera Et Almentioning

confidence: 99%

A Single Residue in the S6 Transmembrane Domain Governs the Differential Flecainide Sensitivity of Voltage-Gated Potassium Channels

Herrera¹,

Mamarbachi²,

Simões³

et al. 2005

Mol Pharmacol

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Flecainide has been used to differentiate Kv4.2-based transient-outward K ϩ -currents (flecainide-sensitive) from Kv1.4-based (flecainide-insensitive). We found that flecainide also inhibits ultrarapid delayed rectifier (I Kur ) currents in Xenopus laevis oocytes carried by Kv3.1 subunits (IC 50 , 28.3 Ϯ 1.3 M) more strongly than Kv1.5 currents corresponding to human I Kur (IC 50 , 237.1 Ϯ 6.2 M). The present study examined molecular motifs underlying differential flecainide sensitivity. An initial chimeric approach pointed to a role for S6 and/or carboxyl-terminal sites in Kv3.1/Kv1.5 sensitivity differences. We then looked for homologous amino acid residues of the two sensitive subunits (Kv4.2 and Kv3.1) different from homologous residues for insensitive subunits (Kv1.4 and Kv1.5). Three candidate sites were identified: two in the S5-S6 linker and one in the S6 segment. Mutation of the proximal S5-S6 linker site failed to alter flecainide sensitivity. Mutation at the more distal site in Kv1.5 (V481L) modestly increased sensitivity, but the reciprocal Kv3.1 mutation (L401V) had no effect. S6 mutants caused marked changes: flecainide sensitivity decreased ϳ8-fold for Kv3.1 L422I (IC 50 , 213 Ϯ 9 M) and increased ϳ7-fold for Kv1.5 I502L (IC 50 , 35.6 Ϯ 1.9 M). Corresponding mutations reversed flecainide sensitivity of Kv1.4 and Kv4.2; L392I decreased Kv4.2 sensitivity by ϳ17-fold (IC 50 of 37.4 Ϯ 6.9 to 628 Ϯ 36 M); I547L increased Kv1.4 sensitivity by ϳ15-fold (IC 50 of 706 Ϯ 37 to 40.9 Ϯ 7.3 M). Our observations indicate that the flecainide sensitivity differences among these four voltagegated K ϩ -channels are determined by whether an isoleucine or a leucine is present at a specific amino acid location.

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Molecular Basis of Ion Selectivity, Block, and Rectification of the Inward Rectifier Kir3.1/Kir3.4 K+ Channel

Cited by 63 publications

References 34 publications

Electrostatic interactions in the channel cavity as an important determinant of potassium channel selectivity

Electrostatic interactions in the channel cavity as an important determinant of potassium channel selectivity

Somatic Mutations Affecting the Selectivity Filter of KCNJ5 Are Frequent in 2 Large Unselected Collections of Adrenal Aldosteronomas

A Single Residue in the S6 Transmembrane Domain Governs the Differential Flecainide Sensitivity of Voltage-Gated Potassium Channels

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