Shah, Mahendrakumar Mala; (2000) The characterization and pharmacology of the slow afterhyperpolarization in cultured rat hippocampal pypramidal cells. Doctoral thesis (Ph.D.), University College London.

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Abstract

Following a burst of action potentials in hippocampal pyramidal cells, a slow afterhyperpolarization (sAHP) is observed which is insensitive to the bee-venom toxin apamin (Sah, 1996). Most of the work published on this response has employed brain slices, the sAHP proving difficult to reproduce in cultured neurones (Alger et al., 1994). In this work, the use of appropriate culture conditions and perforated patch recording has allowed the sAHP to be successfully recorded in cultured neurones. The current underlying the sAHP (SIAHP) in the isolated pyramidal cells was pharmacologically characterized and proved to be similar to that recorded using slices. The SIAHP in these cells was partially inhibited by both L- and N- type calcium channel inhibitors as well as ryanodine, an inhibitor of calcium-induced calcium release. These results suggested that calcium entry via multiple pathways can contribute to the generation of the SIAHP in these cells. The pharmacology of the SIAHP in these cells, as expected, differed greatly from the pharmacology of the apamin-sensitive afterhyperpolarization. The SIAHP could be inhibited by clotrimazole, an antifungal agent which blocks intermediate conductance calcium-activated potassium channels in red blood cells. Two derivatives of clotrimazole, UCL 2027 and UCL 2077, were the most selective blockers of the SIAHP, with very little block of calcium channels. One of the cloned small conductance calcium-activated potassium channel (SK1 channel) has been suggested underlie the SIAHP However, when SK1 cDNA was expressed in mammalian cell lines, the channels formed were apamin-sensitive. UCL 2027 and UCL 2077 also had little effect on the expressed SK1 channels. These results therefore, question whether SK1 channels underlie the SIAHP. In conclusion, two novel blockers of the SIAHP have been identified which may prove useful in establishing the physiological role and in the identification of the molecular correlate of the current.

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