Reference : Electrophysiological characterization of the SK channel blockers methyl-laudanosine and ...
Scientific journals : Article
Human health sciences : Pharmacy, pharmacology & toxicology
http://hdl.handle.net/2268/5149
Electrophysiological characterization of the SK channel blockers methyl-laudanosine and methyl-noscapine in cell lines and rat brain slices
English
Scuvée-Moreau, Jacqueline mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie - Département des sciences biomédicales et précliniques >]
Boland, André mailto [Université de Liège - ULg > Département des sciences cliniques > Gynécologie - Obstétrique >]
Graulich, Amaury [Université de Liège - ULg > > Chimie pharmaceutique >]
Van Overmeire, Lionel mailto [Centre Hospitalier Universitaire de Liège - CHU > > Frais communs médecine >]
D'hoedt, D. [> > > >]
Graulich-Lorge, F. [> > > >]
Thomas, E. [> > > >]
Abras, A. [> > > >]
Stocker, M. [> > > >]
Liégeois, Jean-François mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Seutin, Vincent mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
Nov-2004
British Journal of Pharmacology
Nature Publishing Group
143
6
753-764
Yes (verified by ORBi)
International
0007-1188
London
[en] SK channels ; IK channels ; electrophysiology ; afterhyperpolarization ; monoaminergic neurones ; transfected cell lines ; patch clamp
[en] We have recently shown that the alkaloid methyl-laudanosine blocks SK channel-mediated afterhyperpolarizations (AHPs) in midbrain dopaminergic neurones. However, the relative potency of the compound on the SK channel subtypes and its ability to block AHPs of other neurones were unknown. Using whole-cell patch-clamp experiments in transfected cell lines, we found that the compound blocks SK1, SK2 and SK3 currents with equal potency: its mean IC(50)s were 1.2, 0.8 and 1.8 microM, respectively. IK currents were unaffected. In rat brain slices, methyl-laudanosine blocked apamin-sensitive AHPs in serotonergic neurones of the dorsal raphe and noradrenergic neurones of the locus coeruleus with IC(50)s of 21 and 19 microM, as compared to 15 microM in dopaminergic neurones. However, at 100 microM, methyl-laudanosine elicited a constant hyperpolarization of serotonergic neurones of about 9 mV, which was inconsistently (i.e. not in a reproducible manner) antagonized by atropine and hence partly due to the activation of muscarinic receptors. While exploring the pharmacology of related compounds, we found that methyl-noscapine also blocked SK channels. In cell lines, methyl-noscapine blocked SK1, SK2 and SK3 currents with mean IC(50)s of 5.9, 5.6 and 3.9 microM, respectively. It also did not block IK currents. Methyl-noscapine was slightly less potent than methyl-laudanosine in blocking AHPs in brain slices, its IC(50)s being 42, 37 and 29 microM in dopaminergic, serotonergic and noradrenergic neurones, respectively. Interestingly, no significant non-SK effects were observed with methyl-noscapine in slices. At a concentration of 300 microM, methyl-noscapine elicited the same changes in excitability in the three neuronal types than did a supramaximal concentration of apamin (300 nM). Methyl-laudanosine and methyl-noscapine produced a rapidly reversible blockade of SK channels as compared with apamin. The difference between the IC(50)s of apamin (0.45 nM) and methyl-laudanosine (1.8 microM) in SK3 cells was essentially due to a major difference in their k(-1) (0.028 s(-1) for apamin and >or=20 s(-1) for methyl-laudanosine). These experiments demonstrate that both methyl-laudanosine and methyl-noscapine are medium potency, quickly dissociating, SK channel blockers with a similar potency on the three SK subtypes. Methyl-noscapine may be superior in terms of specificity for the SK channels.
http://hdl.handle.net/2268/5149
also: http://hdl.handle.net/2268/27824
10.1038/sj.bjp.0705979

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