Kv4.2 and Accessory Dipeptidyl Peptidase-like Protein 10 (DPP10) Subunit Preferentially Form a 4:2 (Kv4.2:DPP10) Channel Complex

Kitazawa, Masahiro; Kubo, Yoshihiro; Nakajo, Koichi

doi:10.1074/jbc.m115.646794

Cited by 12 publications

(11 citation statements)

References 66 publications

(87 reference statements)

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“…Considering that the concatemer containing a single silent subunit was functional, we should not exclude ad hoc the possibility of mixed populations. We demonstrated above that Kv2.1/Kv6.4 assemble predominantly in a 2:2 stoichiometry; however, it has been suggested previously that the expression-level ratio between compatible Kv subunits can influence the stoichiometry of heterotetrameric channel complexes in heterologous expression systems (22)(23)(24)(25)(26). Our results above may, thus, be a consequence of the ratio in which Kv2.1 and Kv6.4(-GFP) were expressed.…”

Section: Kv21/kv64 Channels Are Functional In a 3:1 Stoichiometricalmentioning

confidence: 45%

“…Other heterotetrameric Kv channels can assemble with a random subunit stoichiometry and arrangement, depending on the ratio between the involved subunits (22)(23)(24)(25)(26). For example, Kv7.2/Kv7.3 heterotetramers display a fixed 2:2 stoichiometry when cells express an equal amount of both subunits, but varying this ratio results in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, several studies have shown subunit stoichiometry of heteromeric Kv channel complexes to vary dependent on the relative expression of the different subunits (22)(23)(24)(25)(26). It is also important to study only the configuration of functionally expressed Kv2/KvS channel complexes, excluding temporary aggregations that might be formed due to overexpression but that are retained in the endoplasmic reticulum (ER) in a physiological context.…”

Section: Significancementioning

confidence: 99%

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Determining the correct stoichiometry of Kv2.1/Kv6.4 heterotetramers, functional in multiple stoichiometrical configurations

Möller

Regnier

Labro

et al. 2020

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

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The electrically silent (KvS) members of the voltage-gated potassium (Kv) subfamilies Kv5, Kv6, Kv8, and Kv9 selectively modulate Kv2 subunits by forming heterotetrameric Kv2/KvS channels. Based on the reported 3:1 stoichiometry of Kv2.1/Kv9.3 channels, we tested the hypothesis that Kv2.1/Kv6.4 channels express, in contrast to the assumed 3:1, in a 2:2 stoichiometry. We investigate the Kv2.1/Kv6.4 stoichiometry using single subunit counting and functional characterization of tetrameric concatemers. For selecting the most probable stoichiometry, we introduce a model-selection method that is applicable for any multimeric complex by investigating the stoichiometry of Kv2.1/Kv6.4 channels. Weighted likelihood calculations bring rigor to a powerful technique. Using the weighted-likelihood model-selection method and analysis of electrophysiological data, we show that Kv2.1/Kv6.4 channels express, in contrast to the assumed 3:1, in a 2:2 stoichiometry. Within this stoichiometry, the Kv6.4 subunits have to be positioned alternating with Kv2.1 to express functional channels. The variability in Kv2/KvS assembly increases the diversity of heterotetrameric configurations and extends the regulatory possibilities of KvS by allowing the presence of more than one silent subunit.

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Section: Kv21/kv64 Channels Are Functional In a 3:1 Stoichiometricalmentioning

confidence: 45%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Determining the correct stoichiometry of Kv2.1/Kv6.4 heterotetramers, functional in multiple stoichiometrical configurations

Möller

Regnier

Labro

et al. 2020

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

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“…In addition, recent studies have shown that DPP10 genetic variants affect lung function decline in ageing ( Poon et al, 2014 ), and have also been associated with aspirin-exacerbated respiratory disease ( Kim et al, 2015 ). DPP10 is a potassium channel-associated protein ( Chen et al, 2014 ; Kitazawa et al, 2015 ), but unlike other DPP family members, mammalian DPP10 lacks enzymatic activity and is unable to cleave terminal dipeptides from asthma-related cytokines and chemokines ( Allen et al, 2003 ). Interestingly, however, in Drosophila , DPP10 both acts as an ion channel substrate and has peptidase activity ( Shiina et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Manipulation of dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma

Zhang

Poobalasingam

Yates

et al. 2018

Disease Models &Amp; Mechanisms

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We previously identified dipeptidylpeptidase 10 (DPP10) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (Dpp10145D). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies. This article has an associated First Person interview with the first author of the paper.

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“…Similarly, the widely studied KCNE subunits are transmembrane proteins that have been proposed to integrate into clefts between neighboring voltage-sensing domains to modulate channel function (Murray et al, 2016;Wang et al, 2012;Xu et al, 2013) . Another Kv channel with prominent regulation of channel gating by multiple classes of regulatory proteins is the Kv4 family, which is sensitive to both KChIP (a soluble cytoplasmic protein) and DPP-like proteins (transmembrane), leading to modulation of channel expression and gating (Jerng et al, 2005;Kitazawa et al, 2015;Zagha et al, 2005) . Although we have not yet collected direct Slc7a5 regulation of Kv1 channels evidence of an interaction between Slc7a5 and Kv1.1 or Kv1.2, our findings strongly suggest that Slc7a5 sensitivity is encoded by the voltage-sensing domains of these channels.…”

Section: Discussionmentioning

confidence: 99%

Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels

Sharmin

Lamothe

Baronas

et al. 2020

Preprint

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Many voltage-dependent ion channels are regulated by accessory proteins, although the underlying mechanisms and consequences are often poorly understood. We recently reported a novel function of the amino acid transporter Slc7a5 as a powerful regulator of Kv1.2 voltage-dependent activation. In this study, we report that Kv1.1 channels are also regulated by Slc7a5, albeit with different functional outcomes. In heterologous expression systems, Kv1.1 exhibits prominent current enhancement ('disinhibition') with holding potentials more negative than -120 mV. Disinhibition of Kv1.1 is strongly attenuated by shRNA knockdown of endogenous Slc7a5. We investigated a variety of chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to Slc7a5. Overall, our study highlights additional Slc7a5-sensitive Kv1 subunits, and demonstrates that features of Slc7a5 sensitivity can be swapped by exchanging voltage-sensing domains. IMPACT STATEMENT:The voltage-sensing mechanism of a subfamily of potassium channels can be powerfully modulated in unconventional ways, by poorly understood regulatory partners.

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Kv4.2 and Accessory Dipeptidyl Peptidase-like Protein 10 (DPP10) Subunit Preferentially Form a 4:2 (Kv4.2:DPP10) Channel Complex

Cited by 12 publications

References 66 publications

Determining the correct stoichiometry of Kv2.1/Kv6.4 heterotetramers, functional in multiple stoichiometrical configurations

Determining the correct stoichiometry of Kv2.1/Kv6.4 heterotetramers, functional in multiple stoichiometrical configurations

Manipulation of dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma

Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels

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