Abstract
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 [Ca2+]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 (IC50 = 0.5 μM) and in the slice preparation (IC50 ≈ 10 μM). UCL2077 was selective, having minimal effects on Ca2+ channels, action potentials, input resistance and the medium afterhyperpolarization. UCL2077 also had little effect on heterologously expressed small conductance Ca2+-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.
Footnotes
-
This work was supported by the Wellcome Trust and the Medical Research Council.
-
ABBREVIATIONS: mAHP, medium afterhyperpolarization; sAHP, slow afterhyperpolarization; UCL2027, 2-tritylaminothiazole; FCS, fetal calf serum; HEK, human embryonic kidney; sIAHP, slow afterhyperpolarization current; CGP 55,845, (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl] amino-2-hydroxypropyl] (phenylmethyl) phosphinic acid; UCL2077, 3-(triphenylmethylaminomethyl)pyridine; HVA, high-voltage-activated; NMDA, N-methyl-d-aspartate.
- Received May 13, 2006.
- Accepted July 28, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|