Chemical modifications of the N -methyl-laudanosine scaffold point to new directions for SK channels exploration

Badarau, Eduard; Dilly, Sébastien; Seutin, Vincent; Liégeois, Jean François

doi:10.1016/j.bmcl.2014.10.083

Cited by 1 publication

(1 citation statement)

References 31 publications

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“…Similar to benzamil, many inhibitors of SK channels, such as quaternary salts of bicuculline, fluoxetine, NS8593, TEA, methyl-laudanosine and -noscapine, exhibit similar potency on all three homomeric SK channel subtypes (Pedarzani and Stocker, 2008). Their mechanism of inhibition of SK channels varies: pore interactions and block have been proposed for TEA (Dilly et al, 2013;Ishii et al, 1997;Monaghan et al, 2004), methyl-laudanosine (Badarau et al, 2014) and, at the level of the outer pore vestibule, for quaternary salts of bicuculline (Khawaled et al, 1999), while NS8593 acts intracellularly on the Ca 2+ gating molecular machinery (Sorensen et al, 2008). SK channel subtype specificity and mechanism of action are different in the case of apamin, which displays highest affinity for SK2 and lowest for SK1 channels (Pedarzani and Stocker, 2008) and a complex, allosteric inhibitory mechanism, as the toxin interacts with amino acids both within (Ishii et al, 1997;Nolting et al, 2007) and outside the pore region (Lamy et al, 2010;Nolting et al, 2007;Weatherall et al, 2011).…”

Section: Benzamil Directly Inhibits Sk Channelsmentioning

confidence: 99%

Benzamil inhibits neuronal and heterologously expressed small conductance Ca2+-activated K+ channels

et al. 2019

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Small conductance Ca 2+-activated K + (SK) channels are expressed throughout the soma and dendrites of pyramidal neurons in the neocortex and hippocampal formation, where they participate in the local regulation of membrane excitability and synaptic signals. Through their interplay with Ca 2+ channels, SK channels regulate Ca 2+ influx triggered by back-propagating action potentials in dendrites. Inhibition of SK channels affects both the amplitude and duration of Ca 2+ transients, but the role of Ca 2+ clearance mechanisms and their link to SK channel activity has not been established. Here we report the effect of the Na + /Ca 2+ exchanger (NCX) inhibitor benzamil on Ca 2+ extrusion and SK channels in the regulation of dendritic Ca 2+ signals. Benzamil increased the duration and amplitude of dendritic Ca 2+ transients elicited by backpropagating action potentials in hippocampal pyramidal neurons. This data is consistent with previous studies with SK channel blockers and suggests that benzamil inhibits SK channels in addition to the Na + /Ca 2+ exchanger. Here we show that indeed both the neuronal SK-mediated I AHP current and the currents mediated by heterologously expressed SK channels were inhibited by benzamil. The inhibition of recombinant SK channels was seen with different K + concentration gradients, and was stronger at negative voltages. The suppression of SK channels by benzamil is consistent with previous findings on the modulation of Ca 2+ signals by SK channels in neurons. We additionally show that benzamil inhibits neuronal voltage-gated calcium currents. The results prompt a careful reassessment of the effects of benzamil on Ca 2+ transients in native systems, given the spectrum of ion channels and exchangers this compound targets within a similar range of concentrations.

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