Effects of a cognition-enhancer, linopirdine (DuP 996), on M-type potassium currents (IK(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons.
Linopirdine is a cognition enhancer which augments depolarization-induced transmitter release in the cortex and which is under consideration for potential treatment of Alzheimer's disease. It has previously been reported to inhibit M-type K+ currents in rat hippocampal neurons. In the present experiments we have tested its effect on whole-cell M-currents and single M-channels, and on a range of other membrane currents, in dissociated rat superior cervical sympathetic ganglion cells. Linopirdine inhibited the whole-cell M-current with an IC50 of 3.4 microM and blocked M-channels recorded in excised outside-out membrane patches but not in inside-out patches. This suggests that linopirdine directly blocks M-channels from the outside. It was much less effective in inhibiting other voltage-gated potassium currents [delayed rectifier (IK(V)), IC50 63 microM; transient (IA) current, IC50 69 microM] and produced no detectable inhibition of the fast and slow Ca(2+)-activated K+ currents IC and IAHP or of a hyperpolarization-activated cation current (IQ/Ih) at 10-30 microM. However, it reduced acetylcholine-activated nicotinic currents and GABA-activated Cl- currents with IC50 values of 7.6 and 26 microM respectively. It is concluded that linopirdine shows some 20-fold selectivity for M-channels among different K+ channels but can also block some transmitter-gated channels. The relationship between M-channel block and the central actions of linopirdine are discussed.
Lamas
J A
JA
Department of Pharmacology, University College London, UK.
Selyanko
A A
AA
Brown
D A
DA
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005728:Ganglia, Sympathetic / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats
D007211:Indoles; D007473:Ion Channels; D015221:Potassium Channels; D011725:Pyridines; C061017:linopirdine