Essential roles of Homer-1a in homeostatic regulation of pyramidal cell excitability: a possible link to clinical benefits of electroconvulsive shock

Eur J Neurosci. 2005 Jun;21(12):3229-39. doi: 10.1111/j.1460-9568.2005.04165.x.


Homer-1a/Vesl1S, a member of the scaffold protein family Homer/Vesl, is expressed during seizure and serves to reduce seizure susceptibility. Cellular mechanisms for this feedback regulation were studied in neocortex pyramidal cells by injecting Homer-1a protein intracellularly. The injection reduced membrane excitability as demonstrated in two ways. First, the resting potential was hyperpolarized by 5-10 mV. Second, the mean frequency of spikes evoked by depolarizing current injection was decreased. This reduction of excitability was prevented by applying each of the followings: the calcium chelator BAPTA, the calcium store depletor cyclopiazonic acid (CPA), the insitol-1,4,5-trisphosphate receptor (IP(3)R) blocker heparin, the phospholipase C (PLC) inhibitor U-73122, the metabotropic glutamate receptor (mGluR) antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the large-conductance calcium activated potassium channel (BK channel) antagonist charybdotoxin. The small-conductance calcium activated potassium channel (SK channel) blocker dequalinium was ineffective. These findings suggest that activation of mGluR by Homer-1a produced IP(3), which caused inositol-induced calcium release and a consequent BK channel opening, thus hyperpolarizing the injected neurons. In slices from rats subjected to electroconvulsive shock (ECS), a comparable reduction of excitability was observed without Homer-1a injection. The ECS-induced reduction of excitability was abolished by MPEP, charybdotoxin, heparin or BAPTA. Intracellular injection of anti-Homer-1a antibody was suppressive as well, but anti-Homer-1b/c antibody was not. We propose that ECS-induced Homer-1a stimulated the same pathway as did the injected Homer-1a, thereby driving a feedback regulation of excitability.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Animals, Newborn
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / physiology*
  • Charybdotoxin / pharmacology
  • Chelating Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Drug Interactions
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Electroshock / methods*
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Heparin / pharmacology
  • Homer Scaffolding Proteins
  • Membrane Potentials / drug effects
  • Neocortex / cytology
  • Patch-Clamp Techniques / methods
  • Potassium Channel Blockers / pharmacology
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / radiation effects*
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / pharmacology
  • Seizures / drug therapy
  • Seizures / etiology*
  • Time Factors


  • Carrier Proteins
  • Chelating Agents
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Homer Scaffolding Proteins
  • Potassium Channel Blockers
  • Pyridines
  • Recombinant Proteins
  • Charybdotoxin
  • Egtazic Acid
  • 6-methyl-2-(phenylethynyl)pyridine
  • Heparin
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid