Voltage-gated ion channels generate electrical currents that control muscle
contraction, encode neuronal information, and trigger hormonal release.
Tissue-specific expression of accessory (β) subunits causes these channels to
generate currents with distinct properties. In the heart, KCNQ1 voltage-gated
potassium channels coassemble with KCNE1 β-subunits to generate the
IKs current (Barhanin et al.,
1996; Sanguinetti et al., 1996),
an important current for maintenance of stable heart rhythms. KCNE1 significantly
modulates the gating, permeation, and pharmacology of KCNQ1 (Wrobel et al., 2012; Sun et
al., 2012; Abbott, 2014). These
changes are essential for the physiological role of IKs (Silva and Rudy, 2005); however, after 18 years
of study, no coherent mechanism explaining how KCNE1 affects KCNQ1 has emerged. Here
we provide evidence of such a mechanism, whereby, KCNE1 alters the state-dependent
interactions that functionally couple the voltage-sensing domains (VSDs) to the
pore.DOI:
http://dx.doi.org/10.7554/eLife.03606.001
Thus, increased estradiol-17β/ERα signaling in myometrium near term inhibits miR-181a, resulting in a further increase in ERα and proinflammatory signaling. This escalating feedback loop provides novel targets and therapeutic strategies for the prevention of preterm labor and its consequences.
We have miniaturized standard culture techniques to rear arrays of isolated, individual C. elegans throughout their lives on solid gel media. The resulting apparatus is compatible with brightfield and fluorescent microscopy, enabling longitudinal studies of morphology and fluorescent transgene expression. Our culture system exploits a novel crosslinking reaction between a polyethylene glycol hydrogel and a silicone elastomer to constrain animals to individual “corrals” on the gel surface. These devices are simple to construct on the benchtop with commercially available reagents, and, unlike microfluidic isolation methods, does not rely on micropatterned materials. We demonstrate that this new culture method has negligible effects on the physiology of C. elegans compared to standard culture on agar plates. In addition, RNAi techniques are effective in this system. Finally, the hydrogel–silicone binding chemistry that we developed also allows traditional microfluidic devices to be covalently attached to gel substrates instead of glass.
Across species, lifespan is highly variable among individuals within a population. Even genetically identical Caenorhabditis elegans reared in homogeneous environments are as variable in lifespan as outbred human populations. We hypothesized that persistent inter-individual differences in expression of key regulatory genes drives this lifespan variability. As a test, we examined the relationship between future lifespan and the expression of 22 microRNA promoter::GFP constructs. Surprisingly, expression of nearly half of these reporters, well before death, could effectively predict lifespan. This indicates that prospectively long- vs. short-lived individuals have highly divergent patterns of transgene expression and transcriptional regulation. The gene-regulatory processes reported on by two of the most lifespan-predictive transgenes do not require DAF-16, the FOXO transcription factor that is a principal effector of insulin/insulin-like growth factor (IGF-1) signaling. Last, we demonstrate a hierarchy of redundancy in lifespan-predictive ability among three transgenes expressed in distinct tissues, suggesting that they collectively report on an organism-wide, cell non-autonomous process that acts to set each individual’s lifespan.
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