Essential roles of Homer-1a in homeostatic regulation of pyramidal cell excitability: a possible link to clinical benefits of electroconvulsive shock.
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.
Sakagami
Yu
Y
Department of Integrative Brain Science, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Yamamoto
Kenji
K
Sugiura
Shigeki
S
Inokuchi
Kaoru
K
Hayashi
Takuji
T
Kato
Nobuo
N
D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D018999:Charybdotoxin / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004597:Electroshock / Q000379:methods*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D000072233:Homer Scaffolding Proteins; D008564:Membrane Potentials / Q000187:drug effects; D019579:Neocortex / Q000166:cytology; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000528:radiation effects*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012640:Seizures / Q000188:drug therapy / Q000209:etiology*; D013997:Time Factors
D002352:Carrier Proteins; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D000072233:Homer Scaffolding Proteins; D026902:Potassium Channel Blockers; D011725:Pyridines; D011994:Recombinant Proteins; D018999:Charybdotoxin; D004533:Egtazic Acid; C121465:6-methyl-2-(phenylethynyl)pyridine; D006493:Heparin; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid