Concerted All-or-none Subunit Interactions Mediate Slow Deactivation of Human ether-à-go-go-related Gene K+ Channels

Thomson, Steven J.; Hansen, Angela; Sanguinetti, Michael C.

doi:10.1074/jbc.m114.582437

Cited by 12 publications

(5 citation statements)

References 63 publications

(42 reference statements)

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“…When the gating of one subunit in TREK-2 dimer does not alter the gating kinetics of another one, the heterodimers should respond to stimuli in a linear combination for their two homodimers (such as WT-WT and ΔpCt-ΔpCt in our study), and such interactive pattern belongs to independent or sequential manner. If the response of heterodimers to stimuli is similar with those of homodimers, the gating between subunits is compatible with concerted cooperative fashion (Zandany et al, 2008 ; Tombola et al, 2010 ; Meisel et al, 2012 ; Thomson et al, 2014 ). As shown in Figure 2B , 100 μM 2-APB strongly stimulated the currents of WT-ΔpCt, while the activity of ΔpCt-ΔpCt was only slightly stimulated.…”

Section: Resultsmentioning

confidence: 99%

“…If one single mutated subunit is able to eliminate the associated phenotype of WT channel, the concerted cooperativity is negative, the so-called all-or-none mode. Such manner has been found in the activation gate opening of the shaker Kv channel (Zandany et al, 2008 ), the slow deactivation (Thomson et al, 2014 ), C-type inactivation (Wu et al, 2014a ), and drug-binding induced inactivation of human ether-à-go-go-related Gene K + channel 1 (hERG1; Wu et al, 2015b ). Otherwise, if one single WT subunit is sufficient to maintain the phenotype of WT channel, the intersubunit interaction is compatible with positive cooperativity, which means the WT subunit exert positive or dominant effects to the mutated ones.…”

Section: Discussionmentioning

confidence: 97%

“…In multisubunit channels, intersubunit cooperativity might occur during conformational transition in the presence of stimuli or voltage gating. In voltage-dependent K + channels (Kv), it has been established that voltage opens the pore via a concerted cooperative or sequential gating transitions in the tetrameric complex (Tytgat and Hess, 1992 ; Pathak et al, 2005 ; Zandany et al, 2008 ; Gagnon and Bezanilla, 2009 , 2010 ; Yifrach et al, 2009 ; Meisel et al, 2012 ; Thomson et al, 2014 ; Wu et al, 2014a , b ). However, no such progress is made in K2Ps.…”

Section: Introductionmentioning

confidence: 99%

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Intersubunit Concerted Cooperative and cis-Type Mechanisms Modulate Allosteric Gating in Two-Pore-Domain Potassium Channel TREK-2

Zhuo¹,

Peng²,

Liu³

et al. 2016

Front. Cell. Neurosci.

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In response to diverse stimuli, two-pore-domain potassium channel TREK-2 regulates cellular excitability, and hence plays a key role in mediating neuropathic pain, mood disorders and ischemia through. Although more and more input modalities are found to achieve their modulations via acting on the channel, the potential role of subunit interaction in these modulations remains to be explored. In the current study, the deletion (lack of proximal C-terminus, ΔpCt) or point mutation (G312A) was introduced into TREK-2 subunits to limit K+ conductance and used to report subunit stoichiometry. The constructs were then combined with wild type (WT) subunit to produce concatenated dimers with defined composition, and the gating kinetics of these channels to 2-Aminoethoxydiphenyl borate (2-APB) and extracellular pH (pHo) were characterized. Our results show that combination of WT and ΔpCt/G312A subunits reserves similar gating properties to that of WT dimmers, suggesting that the WT subunit exerts dominant and positive effects on the mutated one, and thus the two subunits controls channel gating via a concerted cooperative manner. Further introduction of ΔpCt into the latter subunit of heterodimeric channel G312A-WT or G312A-G312A attenuated their sensitivity to 2-APB and pHo alkalization, implicating that these signals were transduced by a cis-type mechanism. Together, our findings elucidate the mechanisms for how the two subunits control the pore gating of TREK-2, in which both intersubunit concerted cooperative and cis-type manners modulate the allosteric regulations induced by 2-APB and pHo alkalization.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Intersubunit Concerted Cooperative and cis-Type Mechanisms Modulate Allosteric Gating in Two-Pore-Domain Potassium Channel TREK-2

Zhuo¹,

Peng²,

Liu³

et al. 2016

Front. Cell. Neurosci.

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“…Slow deactivation is a fully cooperative process (i.e., all-or-none), requiring the N-C interaction between all four subunits. Disruption of a single N-C interaction is sufficient to greatly accelerate deactivation 34 . This has physiological significance as hERG1 channels can be formed by coassembly of hERG1a subunits that contain a full-length N-terminus and hERG1b subunits that have a truncated N-terminus 4,35 that cannot interact with the C-terminus to slow deactivation.…”

Section: Deactivationmentioning

confidence: 99%

Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology

Sanguinetti

2016

Cardiac Electrophysiology Clinics

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Synopsis Human cardiomyocytes express three distinct types of delayed rectifier potassium channels. hERG1 channels conduct the rapidly activating current IKr, KCNQ1/KCNE1 channels conduct the slowly activating current IKs, and Kv1.5 channels conduct an ultrarapid activating current IKur. Here we provide a general overview of the mechanistic and structural basis of ion selectivity, gating and pharmacology of the three types of cardiac delayed rectifier K+ channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at four symmetrical binding sites outside the cavity.

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“…The inactivation rate was shown to be similar between the two isoforms (Larsen et al, 2008 ). This finding is expected, as the mechanism by which fast inactivation occurs has been proposed to rely mainly on voltage induced changes in the structure of the outer mouth of the pore (Schönherr and Heinemann, 1996 ; Perry et al, 2013a , b ; Thomson et al, 2014 ) and the sequence spanning this region is identical in both isoforms. Lastly, recovery from inactivation is significantly faster in hERG1b compared to hERG1a, potentially implying that by some means, the N-terminus contributes to this process with already proposed stabilizing interactions (Saenen et al, 2006 ; Gustina and Trudeau, 2011 ).…”

Section: Introductionmentioning

confidence: 69%

Determinants of Isoform-Specific Gating Kinetics of hERG1 Channel: Combined Experimental and Simulation Study

et al. 2018

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IKr is the rapidly activating component of the delayed rectifier potassium current, the ion current largely responsible for the repolarization of the cardiac action potential. Inherited forms of long QT syndrome (LQTS) (Lees-Miller et al., 1997) in humans are linked to functional modifications in the Kv11.1 (hERG) ion channel and potentially life threatening arrhythmias. There is little doubt now that hERG-related component of IKr in the heart depends on the tetrameric (homo- or hetero-) channels formed by two alternatively processed isoforms of hERG, termed hERG1a and hERG1b. Isoform composition (hERG1a- vs. the b-isoform) has recently been reported to alter pharmacologic responses to some hERG blockers and was proposed to be an essential factor pre-disposing patients for drug-induced QT prolongation. Very little is known about the gating and pharmacological properties of two isoforms in heart membranes. For example, how gating mechanisms of the hERG1a channels differ from that of hERG1b is still unknown. The mechanisms by which hERG 1a/1b hetero-tetramers contribute to function in the heart, or what role hERG1b might play in disease are all questions to be answered. Structurally, the two isoforms differ only in the N-terminal region located in the cytoplasm: hERG1b is 340 residues shorter than hERG1a and the initial 36 residues of hERG1b are unique to this isoform. In this study, we combined electrophysiological measurements for HEK cells, kinetics and structural modeling to tease out the individual contributions of each isoform to Action Potential formation and then make predictions about the effects of having various mixture ratios of the two isoforms. By coupling electrophysiological data with computational kinetic modeling, two proposed mechanisms of hERG gating in two homo-tetramers were examined. Sets of data from various experimental stimulation protocols (HEK cells) were analyzed simultaneously and fitted to Markov-chain models (M-models). The minimization procedure presented here, allowed assessment of suitability of different Markov model topologies and the corresponding parameters that describe the channel kinetics. The kinetics modeling pointed to key differences in the gating kinetics that were linked to the full channel structure. Interactions between soluble domains and the transmembrane part of the channel appeared to be critical determinants of the gating kinetics. The structures of the full channel in the open and closed states were compared for the first time using the recent Cryo-EM resolved structure for full open hERG channel and an homology model for the closed state, based on the highly homolog EAG1 channel. Key potential interactions which emphasize the importance of electrostatic interactions between N-PAS cap, S4-S5, and C-linker are suggested based on the structural analysis. The derived kinetic parameters were later used in higher order models of cells and tissue to track down the effect of varying the ratios of hERG1a and hERG1b on cardiac action potentials and computed electrocard...

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Concerted All-or-none Subunit Interactions Mediate Slow Deactivation of Human ether-à-go-go-related Gene K+ Channels

Cited by 12 publications

References 63 publications

Intersubunit Concerted Cooperative and cis-Type Mechanisms Modulate Allosteric Gating in Two-Pore-Domain Potassium Channel TREK-2

Intersubunit Concerted Cooperative and cis-Type Mechanisms Modulate Allosteric Gating in Two-Pore-Domain Potassium Channel TREK-2

Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology

Determinants of Isoform-Specific Gating Kinetics of hERG1 Channel: Combined Experimental and Simulation Study

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