Findings provided concurrent validation of the OMNI-RES to measure RPE for the active muscle and overall body in young recreationally trained female and male weight lifters performing upper- and lower-body resistance exercise.
Kv1.3 potassium channels maintain the membrane potential of effector memory (T EM ) T cells that are important mediators of multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. The polypeptide ShK-170 (ShK-L5), containing an N-terminal phosphotyrosine extension of the Stichodactyla helianthus ShK toxin, is a potent and selective blocker of these channels. However, a stability study of ShK-170 showed minor pH-related hydrolysis and oxidation byproducts that were exacerbated by increasing temperatures. We therefore engineered a series of analogs to minimize the formation of these byproducts. The analog with the greatest stability, ShK-192, contains a nonhydrolyzable phosphotyrosine surrogate, a methionine isostere, and a C-terminal amide. ShK-192 shows the same overall fold as ShK, and there is no evidence of any interaction between the N-terminal adduct and the rest of the peptide. The docking configuration of shows the N-terminal para-phosphonophenylalanine group lying at the junction of two channel monomers to form a salt bridge with Lys 411 of the channel. ShK-192 blocks Kv1.3 with an IC 50 of 140 pM and exhibits greater than 100-fold selectivity over closely related channels. After a single subcutaneous injection of 100 g/kg, ϳ100 to 200 pM concentrations of active peptide is detectable in the blood of Lewis rats 24, 48, and 72 h after the injection. ShK-192 effectively inhibits the proliferation of T EM cells and suppresses delayed type hypersensitivity when administered at 10 or 100 g/kg by subcutaneous injection once daily. ShK-192 has potential as a therapeutic for autoimmune diseases mediated by T EM cells.
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by
GRIA1-4
genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca
2+
-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous
de novo GRIA2
mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most
GRIA2
mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that
de-novo
variants in
GRIA2
can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
Background: GABA A R ␣2 and ␥1 subunits are highly expressed in amygdala but their influence on synaptic currents is unknown. Results: ␣2 subunits increased GABA affinity thereby slowing current deactivation; ␥1 subunits reduced synaptic receptor clustering. Conclusion: These subunits may differentially shape synaptic kinetics. Significance: Understanding how ␣2 and ␥1 subunits shape synaptic currents may help us understand amygdala processing mechanisms.
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