期刊
JOURNAL OF NEUROSCIENCE
卷 24, 期 1, 页码 35-42出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3807-03.2004
关键词
sodium current; Scn8a; med; open-channel block; cerebellum; CA3
资金
- NINDS NIH HHS [R01 NS039395, NS39395, R37 NS039395, R56 NS039395, F31 NS045483] Funding Source: Medline
Voltage-gated tetrodotoxin-sensitive sodium channels of Purkinje neurons produce resurgent current with repolarization, which results from relief of an open-channel block that terminates current flow at positive potentials. The associated recovery of sodium channels from inactivation is thought to facilitate the rapid firing patterns characteristic of Purkinje neurons. Resurgent current appears to depend primarily on Na(V)1.6 alpha subunits, because it is greatly reduced in med mutant mice that lack Na(V)1.6. To identify factors that regulate the susceptibility of alpha subunits to open-channel block, we voltage clamped wild-type and med Purkinje neurons before and after slowing conventional inactivation with beta-pompilidotoxin (beta-PMTX). beta-PMTX increased resurgent current in wild-type neurons and induced resurgent current in med neurons. In med cells, the resurgent component of beta-PMTX-modified sodium currents could be selectively abolished by application of intracellular alkaline phosphatase, suggesting that, like in Na(V)1.6-expressing cells, the open-channel block of Na(V)1.1 and Na(V)1.2 subunits is regulated by constitutive phosphorylation. These results indicate that the endogenous blocker exists independently of Na(V)1.6 expression, and conventional inactivation regulates resurgent current by controlling the extent of open-channel block. In Purkinje cells, therefore, the relatively slow conventional inactivation kinetics of Na(V)1.6 appear well adapted to carry resurgent current. Nevertheless, Na(V)1.6 is not unique in its susceptibility to open-channel block, because under appropriate conditions, the non-Na(V)1.6 subunits can produce robust resurgent currents.
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