title: A molecular approach to the calcium signal in brain: relationship to synaptic modulation and seizure discharge.
abstract: The synapse is a major regulatory site that has been implicated in modulating neuronal excitability and seizure discharge. Voltage-dependent calcium (Ca2+) entry at the synapse plays a major role in initiating neurotransmitter release and in regulating synaptic function. Thus, obtaining a molecular understanding of the effects of Ca2+ on synaptic modulation would provide important insights into the regulation of synaptic activity and, possibly, the biochemical basis for some forms of epilepsy. Calmodulin is a major Ca2+-binding protein in brain that has been implicated in mediating many of the second messenger effects of Ca2+ on neuronal function. The evidence implicating calmodulin in modulating synaptic excitability will be presented. Calmodulin was shown to be present at the synapse in association with synaptic vesicles and in the postsynaptic density. In addition, several calmodulin-regulated synaptic biochemical processes have been identified, including Ca2+- and calmodulin-regulated protein phosphorylation, vesicular neurotransmitter release, vesicle-membrane interactions, and neurotransmitter turnover. These results indicate that calmodulin may play an important role in synaptic modulation and provide a molecular approach to investigating the Ca2+ signal in brain. Several anticonvulsants have been shown to regulate some of calcium's effects on neuronal function. These anticonvulsants include phenytoin, carbamazepine, and the benzodiazepines. All of these compounds are effective against maximal electric shock (MES) seizure models in animals. Anticonvulsants were tested on several of the Ca2+-calmodulin-regulated synaptic biochemical systems. The results demonstrate that phenytoin, carbamazepine, and the benzodiazepines were effective in inhibiting calcium calmodulin protein kinase activity in membrane and purified kinase preparations, vesicle neurotransmitter release, vesicle-membrane interactions, and voltage-sensitive calcium uptake in intact synaptosomes. Phenobarbital, ethosuximide, trimethadione, valproic acid, and vinyl gamma-aminobutyric acid (GABA) were not effective in inhibiting these calcium-regulated processes. Thus, the effects of anticonvulsants on calcium-regulated processes were selective to a group of anticonvulsants that had been shown in several electrophysiological systems to antagonize some of the actions of calcium on neuronal excitability. These observations suggested the existence of specific membrane receptors that might mediate the effects of these anticonvulsants on neuronal function through the regulation of calcium-calmodulin-regulated processes.(ABSTRACT TRUNCATED AT 400 WORDS)
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000502:physiology*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002147:Calmodulin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D002220:Carbamazepine / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D006801:Humans; D010672:Phenytoin / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000302:isolation & purification; D011955:Receptors, Drug / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000503:physiopathology*; D013268:Stimulation, Chemical; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D013570:Synaptic Membranes / Q000502:physiology; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000502:physiology
chemical_list: D000927:Anticonvulsants; D002147:Calmodulin; D011955:Receptors, Drug; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D002220:Carbamazepine; D010672:Phenytoin; D011494:Protein Kinases; D003975:Diazepam; D002118:Calcium