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Electrophysiological characterization of the SK channel blockers methyl‐laudanosine and methyl‐noscapine in cell lines and rat brain slices
Author(s) -
ScuvéeMoreau Jacqueline,
Boland Andre,
Graulich Amaury,
Overmeire Lionel Van,
D'hoedt Dieter,
GraulichLorge Fabienne,
Thomas Elizabeth,
Abras Aude,
Stocker Martin,
Liégeois JeanFrancois,
Seutin Vincent
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705979
Subject(s) - afterhyperpolarization , sk channel , apamin , serotonergic , chemistry , neuroscience , locus coeruleus , electrophysiology , dopaminergic , potassium channel , pharmacology , medicine , endocrinology , biology , serotonin , receptor , central nervous system , dopamine , ion channel , biochemistry
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 μ M , 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 μ M , as compared to 15 μ M in dopaminergic neurones. However, at 100 μ M , 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 μ M , 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 μ M 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 μ M , methyl‐noscapine elicited the same changes in excitability in the three neuronal types than did a supramaximal concentration of apamin (300 n M ). 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 n M ) and methyl‐laudanosine (1.8 μ M ) in SK3 cells was essentially due to a major difference in their k −1 (0.028 s −1 for apamin and 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.British Journal of Pharmacology (2004) 143 , 753–764. doi: 10.1038/sj.bjp.0705979