Melatonin (MT) may work as a neuromodulator through the associated MT receptors in the central nervous system. Previously, our studies have shown that MT increased the I K current via a G protein-related pathway. In the present study, patch-clamp whole-cell recording, transwell migration assays and organotypic cerebellar slice cultures were used to examine the effect of MT on granule cell migration. MT increased the I K current amplitude and migration of granule cells. Meanwhile, TEA, the I K channel blocker, decreased the I K current and slowed the migration of granule cells. Furthermore, the effects of MT on the I K current and cell migration were not abolished by pre-incubation with P7791, a specific antagonist of MT 3 R, but were eliminated by the application of the MT 2 R antagonists K185 and 4-P-PDOT. I K current and cell migration were decreased by the application of dibutyryl cyclic AMP (dbcAMP), which was in contrast to the MT effect on the I K current and cell migration. Incubation with dbcAMP essentially blocked the MT-induced increasing effect. Moreover, incubation of isolated cell cultures in the MT-containing medium also decreased the cAMP immunoreactivity in the granule cells. It is concluded, therefore, that I K current, downstream of a cAMP transduction pathway, mediates the migration of rat cerebellar granule cells stimulated by MT.

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2+ release by dantrolene could not decrease the C 6 -ceramide-induced cell death. We therefore suggest that increased PLC-dependent Ca 2+ release through the ryanodine-sensitive Ca 2+ receptor may be responsible for the C 6 -ceramideinduced inhibition of I Na , which does not seem to be associated with C 6 -ceramide-induced granule neuron death.

In this report, the effect of flufenamic acid on voltage-activated transient outward K ϩ current (I A ) in cultured rat cerebellar granule cells was investigated. At a concentration of 20 M to 1 mM, flufenamic acid reversibly inhibited I A in a dose-dependent manner. However, flufenamic acid at a concentration of 0.1 to 10 M significantly increased the current amplitude of I A . In addition to the current amplitude of I A , a higher concentration of flufenamic acid had a significant effect on the kinetic parameters of the steady-state activation and inactivation process, suggesting that the binding affinity of flufenamic acid to I A channels may be state-dependent. Silencing the K v 4.2, K v 4.3, and K v 1.1 genes of I A channels using small interfering RNA did not change the inhibitory effect of flufenamic on I A , indicating that flufenamic acid did not act specifically on any of the subunits of the I A -channel protein. Intracellular application of flufenamic acid could significantly increase the I A amplitude but did not alter the inhibited effect induced by extracellular application of flufenamic acid, implying that flufenamic acid may exert its effect from both the inside and outside sites of the channel. Furthermore, the activation of current induced by intracellular application of flufenamic acid could mimic other cyclooxygenase inhibitors and arachidonic acid. Our data are the first that demonstrate how flufenamic acid is able to bidirectionally modulate I A channels in neurons at different concentrations and by different methods of application and that two different mechanisms may be involved.