Enhancement of Hippocampal Pyramidal Cell Excitability by the Novel Selective Slow-Afterhyperpolarization Channel Blocker 3-(Triphenylmethylaminomethyl)pyridine (UCL2077)

The slow afterhyperpolarization (sAHP) in hippocampal neurons has been implicated in learning and memory. However, its precise role in cell excitability and central nervous system function has not been explicitly tested for 2 reasons: 1) there are, at present, no selective inhibitors that effectivel...

Full description

Saved in:
Bibliographic Details
Published in:Molecular pharmacology 2006-11, Vol.70 (5), p.1494-1502
Main Authors: Shah, Mala M, Javadzadeh-Tabatabaie, Mazyar, Benton, David C H, Ganellin, C Robin, Haylett, Dennis G
Format: Article
Language:English
Subjects:
Action Potentials - drug effects
Animals
Apamin - pharmacology
Benzylamines - pharmacology
Calcium - metabolism
Calcium Channel Blockers - pharmacology
Cells, Cultured
Cloning, Molecular
Humans
Kinetics
Neurons - drug effects
Picolines - pharmacology
Pyramidal Cells - drug effects
Pyramidal Cells - physiology
Pyridines - pharmacology
Rats
Rats, Sprague-Dawley
Small-Conductance Calcium-Activated Potassium Channels - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The slow afterhyperpolarization (sAHP) in hippocampal neurons has been implicated in learning and memory. However, its precise role in cell excitability and central nervous system function has not been explicitly tested for 2 reasons: 1) there are, at present, no selective inhibitors that effectively reduce the underlying current in vivo or in intact in vitro tissue preparations, and 2) although it is known that a small conductance K + channel that activates after a rise in [Ca 2+ ] i underlies the sAHP, the exact molecular identity remains unknown. We show that 3-(triphenylmethylaminomethyl)pyridine (UCL2077), a novel compound, suppressed the sAHP present in hippocampal neurons in culture (IC 50 = 0.5 μM) and in the slice preparation (IC 50 ≈ 10 μM). UCL2077 was selective, having minimal effects on Ca 2+ channels, action potentials, input resistance and the medium afterhyperpolarization. UCL2077 also had little effect on heterologously expressed small conductance Ca 2+ -activated K + (SK) channels. Moreover, UCL2077 and apamin, a selective SK channel blocker, affected spike firing in hippocampal neurons in different ways. These results provide further evidence that SK channels are unlikely to underlie the sAHP. This study also demonstrates that UCL2077, the most potent, selective sAHP blocker described so far, is a useful pharmacological tool for exploring the role of sAHP channels in the regulation of cell excitability in intact tissue preparations and, potentially, in vivo.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.106.026625