Calmodulin systems in neuronal excitability: a molecular approach to epilepsy

Ann Neurol. 1984:16 Suppl:S104-14. doi: 10.1002/ana.410160716.

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+ 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Anticonvulsants / pharmacology
  • Benzodiazepines
  • Brain / physiopathology
  • Calcium / physiology
  • Calcium-Binding Proteins / physiology
  • Calmodulin / physiology*
  • Epilepsy / physiopathology*
  • Humans
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation
  • Receptors, GABA-A / drug effects
  • Synapses / physiology
  • Synaptic Transmission* / drug effects
  • Synaptic Vesicles / physiology

Substances

  • Anti-Anxiety Agents
  • Anticonvulsants
  • Calcium-Binding Proteins
  • Calmodulin
  • Nerve Tissue Proteins
  • Receptors, GABA-A
  • Benzodiazepines
  • Calcium