Differential voltage-dependent modulation of the ACh-gated K+ current by adenosine and acetylcholine

Inhibitory regulation of the heart is determined by both cholinergic M2 receptors (M2R) and adenosine A1 receptors (A1R) that activate the same signaling pathway, the ACh-gated inward rectifier K+ (KACh) channels via Gi/o proteins. Previously, we have shown that the agonist-specific voltage sensitivity of M2R underlies several voltage-dependent features of IKACh, including the ‘relaxation’ property, which is characterized by a gradual increase or decrease of the current when cardiomyocytes are stepped to hyperpolarized or depolarized voltages, respectively. However, it is unknown whether membrane potential also affects A1R and how this could impact IKACh. Upon recording whole-cell currents of guinea-pig cardiomyocytes, we found that stimulation of the A1R-Gi/o-IKACh pathway with adenosine only caused a very slight voltage dependence in concentration-response relationships (~1.2-fold EC50 increase with depolarization) that was not manifested in the relative affinity, as estimated by the current deactivation kinetics (τ = 4074 ± 214 ms at -100 mV and τ = 4331 ± 341 ms at +30 mV; P = 0.31). Moreover, IKACh did not exhibit relaxation. Contrarily, activation of the M2R-Gi/o-IKACh pathway with acetylcholine induced the typical relaxation of the current, which correlated with the clear voltage-dependent effect observed in the concentration-response curves (~2.8-fold EC50 increase with depolarization) and in the IKACh deactivation kinetics (τ = 1762 ± 119 ms at -100 mV and τ = 1503 ± 160 ms at +30 mV; P = 0.01). Our findings further substantiate the hypothesis of the agonist-specific voltage dependence of GPCRs and that the IKACh relaxation is consequence of this property.

Theft-Safe Explosive Mixtures Based on Hydrogen Peroxide: Study of Properties and Built-In Self-Deactivation Kinetics

The current focus on both environmental and general safety is an important issue in the field of explosives. As such, environmentally-friendly explosives, based on hydrogen peroxide (HTP) as an oxidising agent, are of significant interest. These explosives can be designed to undergo self-deactivation, denying access to them by any unlawful third parties that may attempt scavenging blasting sites for any residual energetic materials. Such deactivation also improves blasting safety, as, after a set time, misfired charges no longer pose any explosive threat. In this work, we have designed HTP-based explosive formulations that undergo deactivation after approximately 12 h. To this effect, Al powders were used both as fuels and HTP decomposition promoters. The shock wave parameters and ability to perform mechanical work of the proposed explosive formulations are comparable to those of dynamites and bulk emulsion explosives, and the details of the changes of these parameters over time are also reported.

2-Azabutadiene complexes of rhenium(i): S,N-chelated species with photophysical properties heavily governed by the ligand hidden traits

The S,N-coordination of azabutadienes onto fac-Re(CO)3X species creates moderately emissive complexes, which exhibit ultrafast and multiphasic deactivation kinetics of both their singlet and triplet (MLCT/ILCT) excited states.

Shisa7 is a GABAA receptor auxiliary subunit controlling benzodiazepine actions

The function and pharmacology of γ-aminobutyric acid type A receptors (GABAARs) are of great physiological and clinical importance and have long been thought to be determined by the channel pore–forming subunits. We discovered that Shisa7, a single-passing transmembrane protein, localizes at GABAergic inhibitory synapses and interacts with GABAARs. Shisa7 controls receptor abundance at synapses and speeds up the channel deactivation kinetics. Shisa7 also potently enhances the action of diazepam, a classic benzodiazepine, on GABAARs. Genetic deletion of Shisa7 selectively impairs GABAergic transmission and diminishes the effects of diazepam in mice. Our data indicate that Shisa7 regulates GABAAR trafficking, function, and pharmacology and reveal a previously unknown molecular interaction that modulates benzodiazepine action in the brain.