Calmodulin systems in neuronal excitability: a molecular approach to epilepsy.
Calmodulin is a major Ca2+ -binding protein that may mediate many Ca2+ -regulated processes in neuronal function. Calmodulin is present in the presynaptic nerve terminal in association with synaptic vesicles and in postsynaptic density fractions. Several calmodulin-regulated synaptic biochemical processes have been identified. These results indicate that calmodulin may modulate some aspects of neuronal excitability. Phenytoin, carbamazepine, and the benzodiazepines inhibit Ca2+ -calmodulin-regulated protein phosphorylation and neurotransmitter release by synaptic vesicles. A saturable, stereospecific membrane binding site has been identified for the benzodiazepines. The potency of the benzodiazepines to bind to these sites correlates with their ability to inhibit maximal electroshock-induced seizures. Phenytoin and carbamazepine can displace benzodiazepine binding from these binding sites. Binding to these "anticonvulsant" sites regulates Ca2+ -calmodulin-stimulated membrane protein phosphorylation and depolarization-dependent Ca2+ uptake in intact synaptosome preparations. These results provide evidence that major anticonvulsant drugs regulate Ca2+ -calmodulin systems at the synapse. Kindling alters Ca2+ -calmodulin protein phosphorylation in brain membrane. In addition, alterations in Ca2+ -calmodulin kinase systems have been associated with some strains of seizure-susceptible mice. Thus, evidence from multiple sources suggests that calmodulin-mediated processes may play a role in the development of altered neuronal excitability and in some forms of seizure disorders.
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D001569:Benzodiazepines; D001921:Brain / Q000503:physiopathology; D002118:Calcium / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000502:physiology; D002147:Calmodulin / Q000502:physiology*; D004827:Epilepsy / Q000503:physiopathology*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000187:drug effects; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects; D013572:Synaptic Vesicles / Q000502:physiology
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D002118:Calcium