calcimycin and Seizures

Voltage-dependent Kv2.1 K(+) channels, which mediate delayed rectifier Kv currents (I(K)), are expressed in large clusters on the somata and dendrites of principal pyramidal neurons, where they regulate neuronal excitability. Here we report activity-dependent changes in the localization and biophysical properties of Kv2.1. In the kainate model of continuous seizures in rat, we find a loss of Kv2.1 clustering in pyramidal neurons in vivo. Biochemical analysis of Kv2.1 in the brains of these rats shows a marked dephosphorylation of Kv2.1. In cultured rat hippocampal pyramidal neurons, glutamate stimulation rapidly causes dephosphorylation of Kv2.1, translocation of Kv2.1 from clusters to a more uniform localization, and a shift in the voltage-dependent activation of I(K). An influx of Ca(2+) leading to calcineurin activation is both necessary and sufficient for these effects. Our finding that neuronal activity modifies the phosphorylation state, localization and function of Kv2.1 suggests an important link between excitatory neurotransmission and the intrinsic excitability of pyramidal neurons.

Topics: Animals; Animals, Newborn; Blotting, Western; Cadmium Chloride; Calcimycin; Calcium Channel Blockers; Cell Count; Cells, Cultured; Cyclosporine; Delayed Rectifier Potassium Channels; Dendrites; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Ion Channel Gating; Ionophores; Kainic Acid; Membrane Potentials; Neuronal Plasticity; Nitrendipine; Nitriles; Okadaic Acid; Patch-Clamp Techniques; Phosphoprotein Phosphatases; Phosphorylation; Potassium; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Potassium Chloride; Pyramidal Cells; Pyrethrins; Rats; Seizures; Shab Potassium Channels; Time Factors; Translocation, Genetic

The mechanism of the inhibitory effect of histamine on amygdaloid-kindled seizures was investigated in rats.. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus, and bipolar electrodes were implanted into the right amygdala. A guide cannula made of stainless steel tubing was implanted into the right lateral ventricle. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. EEG was recorded with an electroencephalograph; stimulation of the amygdala was applied bipolarly every day by a constant-current stimulator and continued until a generalized convulsion was obtained.. Intracerebroventricular (i.c.v.) injection of histamine at doses of 2-10 microg resulted in a dose-related inhibition of amygdaloid-kindled seizures. I.c.v. injection of calcium chloride at doses of 10-50 microg and A23187 at doses of 2-10 microg also caused dose-dependent inhibition of amygdaloid-kindled seizures. Calcium chloride at a dose of 10 microg, which showed no significant effect on amygdaloid-kindled seizures when used alone, significantly potentiated the effect of histamine. Similar findings were observed with A23187 at a dose of 2 microg. In addition, EGTA and EGTA/AM antagonized the inhibition of kindled seizures induced by histamine. Moreover, the inhibition of kindled seizures induced by histamine was antagonized by KN62. However, calphostin C did not antagonize the inhibitory effect of histamine.. These results indicated that histamine-induced inhibition of amygdaloid-kindled seizures may be closely associated with a calcium calmodulin-dependent protein kinase II activation pathway.

Topics: Amygdala; Animals; Calcimycin; Calcium Chloride; Egtazic Acid; Electric Stimulation; Electroencephalography; Histamine; Kindling, Neurologic; Male; Naphthalenes; Protein Kinase Inhibitors; Protein Kinases; Rats; Rats, Wistar; Seizures

Cyanide (CN) is a well-recognized poison whose complete actions are unclear. It has been shown that a vasoactive role may be partially responsible for the toxic effects of CN. Sodium nitrite, a known methemoglobin former and vasodilator, has been used to treat CN toxicity. It is rapidly transformed to nitric oxide (NO) which is thought to be endothelium-derived relaxing factor (EDRF). Since the literature suggests that NO can influence the biological effects of CN, studies were undertaken to determine if compounds known to release EDRF/NO will modify CN toxicity. Mice were administered a series of compounds which act through EDRF/NO release. These substances included, platelet-activating factor (PAF), hydralazine, bradykinin, histamine, calcium ionophore A23187, carbachol, or substance P at 0.060, 98.7, 50.0, 125, 1.0, 2.26, and 1.0 mg/kg, respectively. As a control, NG-monomethyl-L-arginine (NMA) 70 mg/kg, which inhibits NO synthesis, was administered to mice iv (tail vein) in combination with each test compound. All test compounds and NMA were administered prior to NaCN: NMA, 5 min; carbachol, 0.5 min; hydralazine, 0.5 min; bradykinin, 1 min; histamine, 1 min; substance P, 4 min; PAF, 5 min; and A23187, 5 min. Dose-response relationships were analyzed by probit dose-response methods and protective ratios for each compound were computed. Results suggest (i) that a portion of the action of CN is affected by a particular EDRF/NO-releasing compound, suggesting that each drug specifically affects regional EDRF/NO receptor sites, and (ii) that NO can play a role as a component in CN intoxication. It is suggested that CN does not act uniformly on all EDRF/NO receptor sites to produce toxicity and site-specific EDRF/NO agents may be useful for treating CN.

Topics: Animals; Bradykinin; Calcimycin; Carbachol; Cyanides; Hydralazine; Ionophores; Lethal Dose 50; Male; Mice; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Platelet Activating Factor; Seizures; Substance P; Survival Rate

Topics: Animals; Anti-Bacterial Agents; Biological Transport, Active; Brain; Calcimycin; Calcium; Catecholamines; Dopamine; Lasalocid; Mitochondria; Norepinephrine; Rabbits; Seizures; Serotonin; Synaptosomes