Pathophysiological Role of K2P Channels in Human Diseases.

The family of two-pore domain potassium (K2P) channels is critically involved in central cellular functions such as ion homeostasis, cell development, and excitability. K2P channels are widely expressed in different human cell types and organs. It is therefore not surprising that aberrant expression and function of K2P channels are related to a spectrum of human diseases, including cancer, autoimmune, CNS, cardiovascular, and urinary tract disorders. Despite homologies in structure, expression, and stimulus, the functional diversity of K2P channels leads to heterogeneous influences on human diseases. The role of individual K2P channels in different disorders depends on expression patterns and modulation in cellular functions. However, an imbalance of potassium homeostasis and action potentials contributes to most disease pathologies. In this review, we provide an overview of current knowledge on the role of K2P channels in human diseases. We look at altered channel expression and function, the potential underlying molecular mechanisms, and prospective research directions in the field of K2P channels.

mTOR signaling in the nucleus accumbens mediates behavioral sensitization to methamphetamine.

Chronic psychostimulant treatment in rodents readily produces behavioral sensitization, which reflects altered brain function in response to repeated drug exposure. Numerous morphological and biochemical investigations implicate altered neural plasticity in striatal medium spiny neurons (MSNs) as an essential component in behavioral sensitization. The mammalian target of the rapamycin (mTOR) signaling pathway, a key regulator of synaptic neuroplasticity, in the ventral striatum of methamphetamine (METH) -sensitized mice was investigated to determine if a link exists with the development of METH sensitization. Behaviorally, METH-sensitized mice possessed increased levels of phosphorylated mTOR/S2448 and its down-stream regulator p70S6K and pS6 in the ventral striatum. Systemic treatment with rapamycin, a specific mTOR inhibitor, coincident with a daily METH injection suppressed the induction of METH sensitization and reduced the number of dendritic spines in the shell and core of the nucleus accumbens. The infusion of lentivirus-expressing mTOR-shRNA into the shell region of the nucleus accumbens inhibited the induction of behavioral sensitization to METH, which was comparable to the effect of rapamycin. These results suggest that mTORC1-mediated signaling in the nucleus accumbens mediates the development of behavioral sensitization to METH.

Aberrant activation of AMP-activated protein kinase contributes to the abnormal distribution of HuR in amyotrophic lateral sclerosis.

Distorted mRNA metabolism contributes to amyotrophic lateral sclerosis (ALS). The human antigen R (HuR) is a major mRNA stabilizer. We report that abnormal localization of HuR was associated with enhanced AMP-activated protein kinase (AMPK) activity in the motor neurons of ALS patients. Activation of AMPK changed the location of HuR in mouse motor neurons and in a motor neuron cell line via phosphorylation of importin-α1. Stimulation of the A2A adenosine receptor normalized the AMPK-evoked redistribution of HuR. This suggests that aberrant activation of AMPK in motor neurons disrupts the normal distribution of HuR, which might imbalance RNA metabolism and contribute to ALS pathogenesis.

Activation of AMP-activated protein kinase α1 mediates mislocalization of TDP-43 in amyotrophic lateral sclerosis.

TAR DNA-binding protein-43 (TDP-43) is a nuclear RNA-binding protein involved in many cellular pathways. TDP-43-positive inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). The major clinical presentation of ALS is muscle weakness due to the degeneration of motor neurons. Mislocalization of TDP-43 from the nucleus to the cytoplasm is an early event of ALS. In this study, we demonstrate that cytoplasmic mislocalization of TDP-43 was accompanied by increased activation of AMP-activated protein kinase (AMPK) in motor neurons of ALS patients. The activation of AMPK in a motor neuron cell line (NSC34) or mouse spinal cords induced the mislocalization of TDP-43, recapitulating this characteristic of ALS. Down-regulation of AMPK-α1 or exogenous expression of a dominant-negative AMPK-α1 mutant reduced TDP-43 mislocalization. Suppression of AMPK activity using cAMP-simulating agents rescued the mislocalization of TDP-43 in NSC34 cells and delayed disease progression in TDP-43 transgenic mice. Our findings demonstrate that activation of AMPK-α1 plays a critical role in TDP-43 mislocalization and the development of ALS; thus, AMPK-α1 may be a potential drug target for this devastating disease.

Next-generation transgenic mice for optogenetic analysis of neural circuits.

Here we characterize several new lines of transgenic mice useful for optogenetic analysis of brain circuit function. These mice express optogenetic probes, such as enhanced halorhodopsin or several different versions of channelrhodopsins, behind various neuron-specific promoters. These mice permit photoinhibition or photostimulation both in vitro and in vivo. Our results also reveal the important influence of fluorescent tags on optogenetic probe expression and function in transgenic mice.

Argonaute identity defines the length of mature mammalian microRNAs.

MicroRNAs (miRNAs) are 19- to 25-nt-long non-coding RNAs that regulate gene expression by base-pairing with target mRNAs and reducing their stability or translational efficiency. Mammalian miRNAs function in association with four closely related Argonaute proteins, AGO1-4. All four proteins contain the PAZ and the MID domains interacting with the miRNA 3' and 5' termini, respectively, as well as the PIWI domain comprising an mRNA 'slicing' activity in the case of AGO2 but not AGO1, AGO3 and AGO4. However, the slicing mode of the miRNA-programmed AGO2 is rarely realized in vivo and the four Argonautes are thought to play largely overlapping roles in the mammalian miRNA pathway. Here, we show that the average length of many miRNAs is diminished during nervous system development as a result of progressive shortening of the miRNA 3' ends. We link this modification with an increase in the fractional abundance of Ago2 in the adult brain and identify a specific structural motif within the PAZ domain that enables efficient trimming of miRNAs associated with this but not the other three Argonautes. Taken together, our data suggest that mammalian Argonautes may define the length and possibly biological activity of mature mammalian miRNAs in a developmentally controlled manner.

Interactions of renin-angiotensin system gene polymorphisms and antihypertensive effect of benazepril in Chinese population.

AIM: Angiotensin-converting enzyme inhibitors are widely used antihypertensive drugs with individual response variation. We studied whether interactions of AGT, AGTR1 and ACE2 gene polymorphisms affect this response. MATERIALS & METHODS: Our study is based on a 3-year field trial with 1831 hypertensive patients prescribed benazepril. Generalized multifactor dimensionality reduction was used to explore interaction models and logistic regressions were used to confirm them. RESULTS: A two-locus model involving the AGT and ACE2 genes was found in males, the sensitive genotypes showed an odds ratio (OR) of 1.9 (95% CI: 1.3-2.8) when compared with nonsensitive genotypes. Two AGT-AGTR1 models were found in females, with an OR of 3.5 (95% CI: 2.0-5.9) and 3.1 (95% CI: 1.8-5.3). CONCLUSION: Gender-specific gene-gene interactions of the AGT, AGTR1 and ACE2 genes were associated with individual variation of response to benazepril. Further studies are needed to confirm this finding.

A genetic epidemiologic study of social support in a Chinese sample.

Accumulated evidence suggests that social support is influenced by genetic and environmental factors. However, there are little data that examine this issue from Asian samples. We reported results from a preliminary study that examined familial effects on social support in a Chinese adult twin sample. We administered a 10-item social support instrument that measures three dimensions of social support (i.e., objective support, subjective support, and utilization of support) developed for the Chinese population. Two hundred forty-two same-sex twin pairs, where both members of the pair completed the personal interview, were included in the final analysis. Structural equation modeling was used to estimate additive genetic (A), shared environmental (C), and nonshared environmental (E) effects on each dimension of social support. Familial factors (A+C) explained 56.63% [95% CI = 45.48-65.72%] and 42.42% [95% CI = 29.93-53.25%] of the total phenotypic variances of subjective support and utilization of support, respectively. For the objective support, genetic effects did not exist, but common environmental effect explained 37.56% [95% CI = 26.17-48.28%] of the total phenotypic variances. Neither gender nor age effects were seen on any dimension of social support. Except for objective support, genetic factors probably influence variation in subjective support and utilization of support. Shared environmental factors may influence all dimensions of social support.

Stroke in China: epidemiology, prevention, and management strategies.

In this review, we examine the current status of stroke epidemiology, prevention, and management strategies in mainland China. The main findings suggested that total age-adjusted incidence of first-ever stroke in China is not very different from that in developed countries. Stroke incidence, mortality, and prevalence varied widely among different regions within China, with a noticeable north-south gradient. The proportion of intracerebral haemorrhage was high and reached 55% in one city. Hypertension is the most important risk factor for stroke. The mass approach combined with a high-risk approach for stroke prevention showed encouraging effects, and various unconventional local therapeutic traditions are commonly used to treat stroke in China. Several national guidelines on stroke prevention and treatment have been developed. Because of methodological limitations in the epidemiology studies, data are unreliable in terms of making any firm conclusions. Up-to-date, well-designed, and well-done epidemiological studies and therapeutic trials in China are urgently needed.