Allosteric effects of external K+ ions mediated by the aspartate of the GYGD signature sequence in the Kv2.1 K+ channel

Chapman, Mark L.; Blanke, Marie L.; Krovetz, Howard S.; VanDongen, Antonius M.J.

doi:10.1007/s00424-005-1515-2

Cited by 9 publications

(8 citation statements)

References 71 publications

(106 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…High affinity permeant ions like Rb + and Cs + (which interact intimately with the selectivity filter) slow down the closure of the internal gate of many K + channels4,16,17. Mutations at or near the selectivity filter lead to a variety of gating effects in K + channels11,18,19,20, while block by the N-terminal inactivating particle, which tends to lock open the inner gate, greatly accelerates entry into the C-type inactivated state3. Experiments on Kir 1.1 have shown that gating by either intracellular protons or extracellular K + ions appear to be coupled through conformational changes near the selectivity filter21.…”

mentioning

confidence: 99%

Structural basis for the coupling between activation and inactivation gates in K+ channels

Cuello

Jogini

Cortés

et al. 2010

Nature

274

442

View full text Add to dashboard Cite

The coupled interplay between activation and inactivation gating is a functional hallmark of K+ channels1,2. This coupling has been experimentally demonstrated from ion interaction effects3,4, cysteine accessibility1 and is associated with a well-defined boundary of energetically coupled residues2. The structure of KcsA in its fully open conformation, as well as four other partial openings, richly illustrates the structural basis of activation-inactivation gating5. Here, we have identified the mechanistic principles by which movements on the inner bundle gate trigger conformational changes at the selectivity filter, leading to the non-conductive C-type inactivated state. Analysis of a series of KcsA open structures suggests that as a consequence of the hinge bending and rotation of TM2, the aromatic ring of Phe103 tilts towards residues Thr74 and Thr75 in the pore helix as well as Ile100 in the neighboring subunit. This allows the network of hydrogen bonds among residues W67, E71, and D80 to destabilize the selectivity filter6,7, facilitating entry to its non-conductive conformation. Mutations at position 103, affect gating kinetics in a size-dependent way: small side chain substitutions F103A and F103C severely impair inactivation kinetics, while larger side chains (F103W) have more subtle effects. This suggests that the allosteric coupling between the inner helical bundle and the selectivity filter might rely on straightforward mechanical deformation propagated through a network of steric contacts. Average interactions calculated from molecular dynamics simulations show favourable open state interaction-energies between Phe103 and surrounding residues. Similar interactions were probed in the Shaker K-channel where inactivation was impaired in the mutant I470A. We propose that side chain rearrangements at position 103 mechanically couple activation and inactivation in KcsA and a variety of other K channels.

show abstract

mentioning

confidence: 99%

Structural basis for the coupling between activation and inactivation gates in K+ channels

Cuello

Jogini

Cortés

et al. 2010

Nature

274

442

View full text Add to dashboard Cite

show abstract

“…The identity of the residue immediately following the second glycine of the selectivity filter motif affects conductance and rectification as well as gating, binding of K + and potency of inhibitors [66], [67]. An aspartate residue at this locus reduces block by Cd 2+ [68] and tetraethylammonium (TEA) [66], suggesting that sensitivity to these and other blockers may differ between GYGD-containing human K + channels and the GYG S -containing protozoan K + channel homologues. These GYG S -containing parasite channels also contain a glutamate residue at an analogous position to the conserved P-loop glutamate residue of K ir channels and KcsA (E138 in K ir 2.1, Figure 2 ) that is involved in gating at the selectivity filter [69], [70].…”

Section: Resultsmentioning

confidence: 99%

Identification of Putative Potassium Channel Homologues in Pathogenic Protozoa

Prole

Marrion

2012

PLoS ONE

View full text Add to dashboard Cite

K+ channels play a vital homeostatic role in cells and abnormal activity of these channels can dramatically alter cell function and survival, suggesting that they might be attractive drug targets in pathogenic organisms. Pathogenic protozoa lead to diseases such as malaria, leishmaniasis, trypanosomiasis and dysentery that are responsible for millions of deaths each year worldwide. The genomes of many protozoan parasites have recently been sequenced, allowing rational design of targeted therapies. We analyzed the genomes of pathogenic protozoa and show the existence within them of genes encoding putative homologues of K+ channels. These protozoan K+ channel homologues represent novel targets for anti-parasitic drugs. Differences in the sequences and diversity of human and parasite proteins may allow pathogen-specific targeting of these K+ channel homologues.

show abstract

“…Furthermore, there is a clear correlation between the occurrence of sub-conductance levels with altered selectivity and mutations in the selectivity filter (Chapman et al, 1997;Zheng and Sigworth, 1997). Mutations at the selectivity filter (Lu et al, 2001) or surrounding structure (Alagem et al, 2003;Chapman et al, 2006;Proks et al, 2001;Sun et al, 1996), showed dramatic effects on rapid gating transitions, while others revealed a large influence in the kinetics and extent of C-type inactivation. Moreover, increasing K + concentration or binding of the blocker TEA in the extracellular region leads to dramatic decrease of C-type inactivation (Baukrowitz and Yellen, 1995;Choi et al, 1991;Lopez-Barneo et al, 1993).…”

Section: 44 Engineering Hydrogen-bond Network In Kv Potassium Channelsmentioning

confidence: 99%

“…Similarly, numerous studies support the role of a network of hydrogen bond interactions behind the selectivity filter during channel gating in a number of K + channels (Kurata and Fedida, 2006;Seebohm et al, 2003). A point mutation in Kv2.1 (D378E, from the GYGD), affects the single channel behavior by the destabilization of the open state (Chapman et al, 2006). Moreover, mutations in the selectivity filter and pore helix of Shaker, hERG, and inward rectifiers also have large effects on gating properties (Alagem et al, 2003;Ficker et al, 1998;Yifrach and MacKinnon, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…A point mutation in Kv2.1 (D378E), equivalent to Asp80 in KcsA, affects the single channel behavior by the destabilization of the open state (Chapman et al, 2006). Moreover, mutations in the selectivity filter and pore helix of Shaker, hERG, and inward rectifiers also have large effects on gating properties (Ficker et al, 1998;Lu et al, 2001;Yifrach and MacKinnon, 2002).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation