GetArtemisininsByAnymeans (GABA)： artemisinins path to conquer diabetes go through GABA receptors

Diabetes is a chronic disease of elevated blood glucose levels that affects more than 400 million people worldwide.Complications of diabetes affect the neuronal and the vascular systems and causes diabetic kidney disease,cardiovascular disease,hypertension,retinopathy,peripheral neuropathy,and diabetic food diseases.Diabetes is caused by either the body’s inability to

How do lateral septum projections to the ventral CA1 influence sociability?

Social dysfunction is a risk factor for several neuropsychiatric illnesses.Previous studies have shown that the lateral septum(LS)-related pathway plays a critical role in mediating social behaviors.Howeve r,the role of the connections between the LS and its downstream brain regions in social behavio rs remains unclea r.In this study,we conducted a three-chamber test using electrophysiological and chemogenetic approaches in mice to determine how LS projections to ventral CA1(vCA1)influence sociability.Our res ults showed that gamma-aminobutyric acid(GABA)-e rgic neuro ns were activated following social experience,and that social behavio rs were enhanced by chemogenetic modulation of these neurons.Moreover,LS GABAergic neurons extended their functional neural connections via vCA1 glutamatergic pyramidal neurons,and regulating LSGABA→vCA1Gluneural projections affected social behaviors,which were impeded by suppressing LSprojecting vCA1 neuronal activity or inhibiting GABAAreceptors in vCA1.These findings support the hypothesis that LS inputs to the vCA1 can control social prefe rences and social novelty behaviors.These findings provide new insights rega rding the neural circuits that regulate sociability.

Diazepam reduces synaptic GABA type areceptor availability via multiple trafficking mechanisms

OBJECTIVE Investigate the effects of diazepam(DZP) on γ2 subunit containing GABA type A receptor(GABA A R) trafficking.METHODS Immunofluorescence microscopy measured surface GABA A Rs and gephyrin in rat cortical neurons after 24 h exposure of 1.0 μmol·L^(-1) DZP.Biochemical studies of mice injected with 10 mg·kg^(-1) DZP vs vehicle were assessed for γ2 subunit and total gephyrin cortical levels 12 h post-injection.Ubiquitination of the γ2 subunit was studied by immunoprecipitation after 12 h of 1.0 μmol·L^(-1) DZP exposure.A γ2 subunit encoding an N terminal fluorogen-activating peptide and pH-sensitive green fluorescent protein(γ2 pH FAP) measured lysosomal targeting of γ2 containing GABA A Rs.RFP-gephyrin and γ2 pH FAP synaptic diffusion rates were examined using fluorescence recovery after photobleaching(FRAP).RESULTS Extrasynaptic levels of γ2 GABA A Rs decreased by 12.2%,while synaptic gephyrin S270 phosphorylation increased by 18.3% in DZP-treated neurons after 24 h compared to control(P<0.05).Dendritic levels of gephyrin were also reduced to 74.1% of control,while S270 phosphorylation was elevated by 25.2%(P<0.05;P<0.01).Mice 12 h post-DZP injection demonstrated a 12.7% and 26.1% decrease in total γ2 and gephyrin levels,respectively(P<0.05;P<0.01).12 h DZP treatment enhanced γ2 subunit ubiquitination 1.13-fold relative to control(P<0.05).Internalized γ2 pH FAP GABA A Rs associated with lysosomes was 8.0% higher in neurons treated with 12-16 h DZP compared to control.Pilot FRAP experiments suggest gephyrin and γ2 have increased mobility and turnover at synapses following DZP.CONCLUSION DZP treatment decreases γ2 GABA A R levels and gephyrin scaffolding function after one day of exposure,which may contribute to the formation of DZP tolerance.

Electroacupuncture-induced activation of GABAergic system alleviates airway inflammation in asthma model by suppressing TLR4/MyD88/NF-κB signaling pathway

Background: Electroacupuncture (EA) has been shown to attenuate airway inflammation in asthmatic mice;however, the underlying mechanism is not fully understood. Studies have shown that EA can significantly increase the inhibitory neurotransmitter γ-aminobutyric acid (GABA) content in mice, and can also increase the expression level of GABA type A receptor (GABAAR). Furthermore, activating GABAAR may relieve inflammation in asthma by suppressing toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling pathway. Therefore, this study aimed to investigate the role of GABAergic system and TLR4/MyD88/NF-κB signaling pathway in asthmatic mice treated with EA. Methods: A mouse model of asthma was established, and a series of methods including Western blot and histological staining assessment were employed to detect the level of GABA, and expressions of GABAAR and TLR4/MyD88/NF-κB in lung tissue. In addition, GABAAR antagonist was used to further validate the role and mechanism of GABAergic system in mediating the therapeutic effect of EA in asthma. Results: The mouse model of asthma was established successfully, and EA was verified to alleviate airway inflammation in asthmatic mice. The release of GABA and the expression of GABAAR were significantly increased in asthmatic mice treated with EA compared with untreated asthmatic mice ( P < 0.01), and the TLR4/MyD88/NF-κB signaling pathway was down-regulated. Moreover, inhibition of GABAAR attenuated the beneficial effects of EA in asthma, including the regulation of airway resistance and inflammation, as well as the inhibitory effects on TLR4/MyD88/NF-κB signaling pathway. Conclusion: Our findings suggest that GABAergic system may be involved in mediating the therapeutic effect of EA in asthma, possibly by suppressing the TLR4/MyD88/NF-κB signaling pathway.

Novel alternative splicing of GABA receptor RDL exon 9 from Laodelphax striatellus modulates agonist potency

The resistance to dieldrin gene(RDL)encodes the primary subunit of the insect ionotropic y-aminobutyric acid(GABA)receptor(GABAR),which is the target of phenylpyrazole and isoxazoline insecticides.The splice variants in exons 3 and 6 of RDL,which have been widely explored in many insects,modulate the agonist potency of the homomeric RDL GABAR and potentially play an important role in the development of insects.In the present study,four splice variants of exon 9 were identified in RDL of the small brown planthopper,Laodelphax striatellus(LsRDL),resulting in LsRDL-9sl,LsRDL-92l\LsRDL-9b,and LsRDL-9c.LsRDL-9a has one more amino acid(E,glutamic acid)compared with LsRDL-9a\and LsRDL-9b lacked two amino acids and had seven different amino acids compared with LsRDL-9c.Two-electrode voltage-clamp recording on LsRDLs expressed in Xenopus oocytes showed that alternative splicing of exon 9 has significant impact on LsRDL sensitivity to the agonists GABA and 0-alanine,whereas no significant difference was observed in the potencies of the non-competitive antagonists(NCAs)ethiprole and fluralaner on the splice variants.Our results suggest that alternative splicing of RDL exon 9 broadens functional capabilities of the GABAR in L.striatellus by influencing the action of GABA.

The language of GABA in pollen tube growth and guidance

The achievement of double fertilization in higher plants requires the successful transport of sperm cells to the female gametes,the ovules.Pollen tubes,the tubular structure protruding from pollens,carrying the sperms play an important role in this process.How a pollen tube precisely guides its direction to gain its goal is of mystery.Previous investigation indicated that multiple signal clues from the pistils function as the route signs to regulate the pathway of pollen tube growth.Among the signal clues,c-aminobutyric acid(GABA)seems to be universal.Its gradient concentration has been found both in tobacco and Arabidopsis pollen tube guidance.In the communication of pollens and pistils,what on earth GABA tells pollen tubes is of great interest.The GABA receptors on the pollen membrane are thought to be the hinge in the language conversation.In this review,the mechanism of GABA gradient formation is investigated.The possible GABA receptor on the pollen membrane is examined and its function is discussed.To decipher the possible language of GABA in pollen tube growth and guidance,multiple methods are needed.The combination of transcriptome and proteomics assay is expected to unveil the secret.