Presynaptic External Calcium Signaling Involves the Calcium-Sensing Receptor in Neocortical Nerve Terminals

Nerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca(2+)] ([Ca(2+)](o)) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca(2+)](o) sensor. Here, we identify the first component in a presynaptic calcium signaling pathway.By combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca(2+)](o) than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents.Our experiments identify CaSR as the first component in the [Ca(2+)](o) sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca(2+)](o) will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca(2+)](o) following its entry via voltage-activated Ca(2+) channels. CaSR may detects such falls in [Ca(2+)](o) and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca(2+)](o) on release probability. CaSR is positioned to detect the dynamic changes of [Ca(2+)](o) and provide presynaptic feedback that will alter brain excitability

Synthesis of nonsymmetrical 5-aryl-2-indolopyrrole derivatives via controlled mono Suzuki-Miyaura cross-coupling on N-Boc-2,5-dibromopyrrole

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Enantioselective intramolecular copper-catalyzed aziridination of sulfamates

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Redox-responsive catalysis: fine tuning of chemoselectivity in the intramolecular reaction of diazo compounds catalysed by ferrocene-functionalised dirhodium(II) complexes

International audienceA series of heteroleptic dirhodium(II) complexes (1a–k) of formula [Rh2(OAc)3(L)], where L is a redox-active ferrocenecarboxylate ligand, have been evaluated in the redox-responsive, dirhodium(II)-catalysed decomposition of several diazo substrates prone to chemoselectivity issues. The influence of the counter-anion of chemically oxidised ferrocenyl-containing complexes on the chemoselectivity of the decomposition of the diazo compound 2 has been investigated with complexes 1a–d: bulky, weakly coordinating SbF6− and BArF4− ([(3,5-(CF3)2C6H3)4B]−) result in a greater chemoselectivity difference between the reduced and oxidised versions of the catalyst than BF4−. The correlation between the electronic nature of the ferrocenyl substituents and the extent of the chemoselectivity switch is not obvious, as complex 1a with unsubstituted ferrocene gave the best results upon oxidation among complexes 1a–k. The introduction of a saturated tether in 1j–k drastically decreases the chemoselectivity difference between the reduced and oxidised species. Finally, two additional diazo compounds with various chemoselectivity issues (9 and 10) were evaluated in the presence of complexes 1a and 1a+·SbF6−: the decomposition of diazo complex 9, producing an aromatic C–H insertion product 11 and a cyclopropanation product 12, led to a 42% chemoselectivity difference between 1a and 1a+·SbF6−. This demonstrates that changing the electronic properties of only one ligand on dirhodium, by oxidation of its ferrocenyl part, can have a marked influence on the reaction selectivity

Synthesis of Aziridinosteroids

Abstract: 11α,12α-aziridinosteroids (2a, b, c) were prepared from 5β-H-11-pregnene-3, 20-dione (1) using different iminophenyliodinanes and cloramine aziridination reagents