Cell Cycle–related Changes in the Conducting Properties of r-eag K+ Channels

Pardo, Luis A.; Brüggemann, Andrea; Camacho, Javier; Stühmer, Walter

doi:10.1083/jcb.143.3.767

Cited by 110 publications

(105 citation statements)

References 44 publications

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“…In addition, cell cycle regulation of exogenously expressed channel proteins in Xenopus oocytes has been reported. The rat ether-a-go-go K ϩ channel alters its voltage dependence during meiotic maturation through an MPF-mediated process (32). However, to our knowledge, none of these currents exhibit a similar regulation to the rapid and complete inactivation observed for SOCE.…”

Section: Resultsmentioning

confidence: 84%

Store-operated Calcium Entry Inactivates at the Germinal Vesicle Breakdown Stage of Xenopus Meiosis

Machaca

Haun

2000

Journal of Biological Chemistry

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Store-operated calcium entry (SOCE) is the predominant Ca2؉ influx pathway in non-excitable cells and is activated in response to depletion of intracellular Ca 2؉ stores. We have studied SOCE regulation during Xenopus oocyte meiosis. SOCE can be measured readily in stage VI Xenopus oocytes arrested at the G 2 -M transition of the cell cycle, either by Ca 2؉ imaging or by recording the SOCE current. However, following meiotic maturation, SOCE can no longer be activated by store depletion. We have characterized the time course of SOCE inactivation during oocyte maturation, and show that SOCE inactivates almost completely, in a very short time period, at the germinal vesicle breakdown stage of meiosis. This acute inactivation offers an opportunity to better understand SOCE regulation.Ionic calcium (Ca 2ϩ ) is a universal second messenger important for many cellular responses ranging from gene expression to fertilization (1). Ca 2ϩ signaling is mediated by a rise in cytoplasmic Ca 2ϩ , either by Ca 2ϩ release from intracellular stores or Ca 2ϩ influx from the extracellular space. In nonexcitable cells the primary Ca 2ϩ influx pathway is store-operated calcium entry (SOCE) 1 (2). SOCE is activated in response to depletion of intracellular calcium stores and has been implicated in several cellular processes, including T-cell activation (3, 4) and regulation of exocytosis (5-7). However the mechanism(s) coupling store depletion to SOCE activation remain unknown. The following three models have been proposed: "physical coupling," "diffusible messenger," and "vesicle fusion." The physical coupling hypothesis proposes that SOCE channels couple directly to a Ca 2ϩ sensor on the endoplasmic reticulum membrane, possibly the IP 3 receptor, in analogy to the dihydropyridine-ryanodine receptor interaction in skeletal muscle (8 -10). Whereas the diffusible messenger hypothesis argues that store depletion results in the generation of a diffusible messenger that opens SOCE channels (11-13), the vesicle fusion model proposes that SOCE channels are inserted in the plasma membrane following store depletion (14). Although there is some evidence for each model (2), it is not yet clear what the coupling mechanism is and whether SOCE is activated by the same mechanism in different cell types.Despite the importance and ubiquitous nature of Ca 2ϩ signaling pathways, their role and regulation during the cell cycle remain controversial. Probably the clearest example of a Ca 2ϩ requirement during the cell cycle is at fertilization, where a Ca 2ϩ signal is necessary and sufficient for egg activation and the initiation of embryonic development (15, 16). Oocytes of both Xenopus and mammals are arrested at the G 2 -M transition of the cell cycle (15, 17). Before such oocytes become competent to be fertilized and able to support embryonic development, they undergo a maturation process called meiotic (or oocyte) maturation. During this maturation period oocytes enter meiosis, complete the first meiotic division with the extrusion of a polar body,...

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Section: Resultsmentioning

confidence: 84%

Store-operated Calcium Entry Inactivates at the Germinal Vesicle Breakdown Stage of Xenopus Meiosis

Machaca

Haun

2000

Journal of Biological Chemistry

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“…As such, ion channel expression and function may vary depending on the cell cycle phase. For example, a previous study demonstrated that EAG1 expression is dependent on the cell cycle in human neuroblastoma cells (Meyer and Heinemann 1998), and a heterologous expression study in Xenopus oocytes has demonstrated changes in the electrophysiological properties of rat Eag1 that depend on the mitosis-promoting factor (Pardo et al 1998). Similarly, the expression and voltage dependence of HERG channel activation differ during the cell cycle, which may reflect another venue for dynamic regulation of cell proliferation (Arcangeli et al 1995;Crociani et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

et al. 2012

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Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.

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“…1 was used. Since rectification can be attributed to block by intracellular sodium (Pardo et al 1998), it can (and does) vary from oocyte to oocyte. Fitting the parameters of Eq.…”

Section: Current-voltage Relationship In the Absence Of External Magnmentioning

confidence: 99%

The voltage dependence of hEag currents is not determined solely by membrane-spanning domains

et al. 2008

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The ether-à-go-go potassium channels hEag1 and hEag2 are highly homologous. Even though both possess identical voltage-sensing domain S4, the channels act differently in response to voltage. Therefore we asked whether transmembrane domains other than the voltage sensor could contribute to the voltage-dependent behaviour of these potassium channels. For this chimaeras were created, in which each single transmembrane domain of hEag1 was replaced by the corresponding segment of hEag2. The voltage-dependent properties of the chimaeras were analysed after expression in Xenopus laevis oocytes using the two-electrode voltage-clamp method. By this we found, that only the mutations in transmembrane domains S5 and S6 are able to change the voltage sensitivity of hEag1 by shifting the half-activation potential (V 50 ) to values intermediate between the two wild types. Moreover, the presence of Mg 2+ has strong effects on the voltage sensitivity of hEag2 shifting V 50 by more than 50 mV to more positive values. Interestingly, despite the identical binding site Mg 2+ showed only little effects on hEag1 or the chimaeras. Altogether, our data suggest that not only transmembrane spanning regions, but also non-membrane spanning regions are responsible for differences in the behaviour of the hEag1 and hEag2 potassium channels.

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Cell Cycle–related Changes in the Conducting Properties of r-eag K+ Channels

Cited by 110 publications

References 44 publications

Store-operated Calcium Entry Inactivates at the Germinal Vesicle Breakdown Stage of Xenopus Meiosis

Store-operated Calcium Entry Inactivates at the Germinal Vesicle Breakdown Stage of Xenopus Meiosis

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

The voltage dependence of hEag currents is not determined solely by membrane-spanning domains

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