Calmodulin systems in neuronal excitability: A molecular approach to epilepsy

Abstract

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⁺ -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 seizuresusceptible 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.