Abstract
Small-conductance Ca2+-activated K+ channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-laudanosine, and ethyl-laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC50 values of 152, 15, and 47 μM, respectively. The benzyl and butyl derivatives were less potent. Methyl-laudanosine had no effect on the Ih current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABAA receptors. Interestingly, 100 μM methyl-laudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC504 μM) is superior to its affinity for muscarinic (IC50114 μM) and neuronal nicotinic (IC50 ≥367 μM) receptors . Methyl-laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models.
Footnotes
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This work was supported in part by Grant 3.4525.98 from the National Fund for Scientific Research (Brussels, Belgium). This work has been presented in meeting abstract form: Scuvée-Moreau J, Liégeois JF, and Seutin V (2002) Effect of laudanosine derivatives on the apamin-sensitive afterhyperpolarization of rat dopaminergic neurons—identification of methyl-laudanosine as a new specific blocker (Abstract). Fundam Clin Pharmacol16:67.
- Abbreviations:
- SK channels
- small-conductance voltage-insensitive Ca2+-activated K+ channels
- AHP
- afterhyperpolarization
- ZD7288
- 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)-pyrimidinium chloride
- SR95531
- 2-[carboxy-3′-propyl]-3-amino-6-paramethoxy-phenyl-pyridazinium bromide
- Received November 13, 2001.
- Accepted May 15, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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