SYMPOSIUM REVIEW: Gating of two pore domain potassium channels

Mathie, Alistair; Al‐Moubarak, Ehab; Veale, Emma L.

doi:10.1113/jphysiol.2010.192344

Cited by 77 publications

(76 citation statements)

References 52 publications

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“…In the case of SMCs, mutation of cohesin accessory factors can impair neuronal and axonal migration in C. elegans and mice (30). Non-twk potassium channels are required for mammalian cell migration (43), and mammalian TWK channels are activated by both chemical and mechanical stimuli (44); mammalian TWK channels, like their C. elegans orthologs, could also have a migratory function. Similarly to NHR-67 in the LC, regulators of the actin and microtubule cytoskeleton are transcriptionally up-regulated by SLBO in migrating Drosophila border cells (7,8).…”

Section: Discussionmentioning

confidence: 99%

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Schwarz

Kato

Sternberg

2012

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

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In both metazoan development and metastatic cancer, migrating cells must carry out a detailed, complex program of sensing cues, binding substrates, and moving their cytoskeletons. The linker cell in Caenorhabditis elegans males undergoes a stereotyped migration that guides gonad organogenesis, occurs with precise timing, and requires the nuclear hormone receptor NHR-67. To better understand how this occurs, we performed RNA-seq of individually staged and dissected linker cells, comparing transcriptomes from linker cells of third-stage (L3) larvae, fourth-stage (L4) larvae, and nhr-67-RNAi-treated L4 larvae. We observed expression of 8,000-10,000 genes in the linker cell, 22-25% of which were up-or downregulated 20-fold during development by NHR-67. Of genes that we tested by RNAi, 22% (45 of 204) were required for normal shape and migration, suggesting that many NHR-67-dependent, linker cell-enriched genes play roles in this migration. One unexpected class of genes up-regulated by NHR-67 was tandem pore potassium channels, which are required for normal linker-cell migration. We also found phenotypes for genes with human orthologs but no previously described migratory function. Our results provide an extensive catalog of genes that act in a migrating cell, identify unique molecular functions involved in nematode cell migration, and suggest similar functions in humans.major sperm protein | nematode development | transcriptional profiling | twin pore potassium channels | conserved uncharacterized proteins C ell migration is pervasive in animal development and is also an unwanted part of human cancer. Several different varieties of cell migration, ranging from social protozoa to the human immune system, have been extensively studied (1), but there remains a need for detailed analysis of the different components of migration in a simple cell type that can be exhaustively probed through anatomy, genetics, and genomics. We have undertaken to develop the linker cell (LC) of Caenorhabditis elegans as such a model. The LC is a single cell, attached to the front of a proliferating male gonad, which carries out a stereotypic, long-range migration to generate the shape of the mature gonad (Fig. 1A). During 25 h of the second to fourth larval stages (L2 through L4), the LC moves anteriorly along the ventral body wall, turns dorsally, proceeds posteriorly, switches sides once more to the ventral bodywall, continues posteriorward, reaches the cloaca, and eventually dies (2-4). Throughout this process, the proliferating and lengthening male gonad follows the LC's path to the cloaca. Stage-specific changes occur during the middle to late stages of migration (L3 and L4 larval stages): the LC changes shape from a spheroid to a pointed ellipsoid; it increases its speed of migration; and the netrin receptor gene unc-5 is down-regulated within the LC, which causes it to switch body walls ventrally ( Fig. 1A; ref. 3). These changes between the L3 and L4 stages require the orphan nuclear receptor NHR-67, whose orthologs TAILLESS and TLX...

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Section: Discussionmentioning

confidence: 99%

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Schwarz

Kato

Sternberg

2012

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

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“…The variant is localized in the first pore-forming loop, a region adjacent to the selectivity filter and is also implicated in K 2P channel gating (Fig. 1A) (Brohawn et al 2012;Mathie et al 2010;Miller and Long 2012;Piechotta et al 2011). We tagged the WT, MT, and CR TRESK subunits with EGFP or mCherry at the NH 2 terminus so as to study the effects of the CR variant on the biophysical properties as well as the expression level of TRESK channels.…”

Section: Dominant-negative Effect Of the Tresk Cr Variant On Whole Cementioning

confidence: 99%

Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

Guo

Liu

Ren

et al. 2014

Journal of Neurophysiology

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Guo Z, Liu P, Ren F, Cao YQ. Nonmigraine-associated TRESK K ϩ channel variant C110R does not increase the excitability of trigeminal ganglion neurons. J Neurophysiol 112: 568 -579, 2014. First published May 7, 2014 doi:10.1152/jn.00267.2014.-Recent genetic studies suggest that dysfunction of ion channels and transporters may contribute to migraine pathophysiology. A migraineassociated frameshift mutation in the TWIK-related spinal cord K ϩ (TRESK) channel results in nonfunctional channels. Moreover, mutant TRESK subunits exert a dominant-negative effect on whole cell TRESK currents and result in hyperexcitability of small-diameter trigeminal ganglion (TG) neurons, suggesting that mutant TRESK may increase the gain of the neuronal circuit underlying migraine headache. However, the nonmigraine-associated TRESK C110R variant exhibits the same effect on TRESK currents as the mutant subunits in Xenopus oocytes, suggesting that dysfunction of TRESK is not sufficient to cause migraine. Here, we confirmed that the C110R variant formed nonfunctional channels and exerted a dominant-negative effect on TRESK currents in HEK293T cells, similar to the migraine-associated mutant TRESK. To compare the functional consequences of TRESK mutations/variants in a more physiological setting, we expressed the mutant TRESK and the C110R variant in cultured mouse TG neurons and investigated their effects on background K ϩ currents and neuronal excitability. Both mutant TRESK and the C110R variant reduced the endogenous TRESK currents in TG neurons, but the effect of the C110R variant was significantly smaller. Importantly, only TG neurons expressing mutant TRESK subunits, but not those expressing the C110R variant, exhibited a significant increase in excitability. Thus only the migraine-associated TRESK mutation, but not the C110R variant, reduces the endogenous TRESK currents to a degree that affects TG excitability. Our results support a potential causal relationship between the frameshift TRESK mutation and migraine susceptibility.

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“…By contrast, the gating of K2P channels was thought to occur through their upper gate [56][57][58][59]. However, except for the upper gate, recent evidence shows that K2P channels may also possess a lower bundle-crossing gate, similar to Kv channels [59][60][61]. For TASK3 channels, the pore-lining helices consisting of two highly conserved putative hinge glycines form the lower gate and mutations of these glycines affect channel opening [62].…”

Section: Discussionmentioning

confidence: 99%

Grafting voltage and pharmacological sensitivity in potassium channels

Lan

Fan

et al. 2016

Cell Res

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A classical voltage-gated ion channel consists of four voltage-sensing domains (VSDs). However, the roles of each VSD in the channels remain elusive. We developed a GVTDT (Graft VSD To Dimeric TASK3 channels that lack endogenous VSDs) strategy to produce voltage-gated channels with a reduced number of VSDs. TASK3 channels exhibit a high host tolerance to VSDs of various voltage-gated ion channels without interfering with the intrinsic properties of the TASK3 selectivity filter. The constructed channels, exemplified by the channels grafted with one or two VSDs from Kv7.1 channels, exhibit classical voltage sensitivity, including voltage-dependent opening and closing. Furthermore, the grafted Kv7.1 VSD transfers the potentiation activity of benzbromarone, an activator that acts on the VSDs of the donor channels, to the constructed channels. Our study indicates that one VSD is sufficient to voltage-dependently gate the pore and provides new insight into the roles of VSDs.

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SYMPOSIUM REVIEW: Gating of two pore domain potassium channels

Cited by 77 publications

References 52 publications

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

Grafting voltage and pharmacological sensitivity in potassium channels

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SYMPOSIUM REVIEW: Gating of two pore domain potassium channels

Cited by 77 publications

References 52 publications

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

Grafting voltage and pharmacological sensitivity in potassium channels

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Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons