SEIZURES INDUCE THE FORMATION OF HETEROMERIC HCNs (HYPERPOLARIZATION ACTIVATED cAMP GATED CHANNELS): A NOVEL MECHANISM FOR [lsquo]CHANNELOPATHIES[rsquo]?
Abstract number :
2.047
Submission category :
Year :
2003
Submission ID :
3661
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Amy L. Brewster, Joie A. Bernard, Christine M. Gall, Tallie Z. Baram Anatomy and Neurobiology, University of California-Irvine; Pediatrics, University of California-Irvine, Irvine, CA
Hyperpolarization activated cAMP gated channels (HCNs) mediate the I[sub]h[/sub] current that contributes critically to intrinsic neuronal properties and neuronal network excitability. Hippocampal HCN channels are composed of four homomeric subunits. We have previously implicated altered expression of two HCN family members (HCN1 and 2) in experimental epileptogenesis after febrile seizures, where I[sub]h[/sub] with novel properties has been characterized. However, the precise molecular basis for this modified I[sub]h[/sub] has remained unclear. Here we test the hypothesis that the altered relative expression of HCN1 and HCN2 results in formation of novel heteromeric channels.
Co-immunoprecipitation of HCN1 and HCN2 was performed on control hippocampi and on tissue from rats that had sustained experimental febrile or kainate-induced seizures (lasting 20 and 180 minutes, respectively) one or four weeks earlier.
In control hippocampi, precipitation of HCN2 produced only modest evidence of its co-association with HCN1. In contrast, a striking increase in co-immunoprecipitation of HCN1 and HCN2 occurred in hippocampal tissue from seizure-experiencing animals, and persisted for at least four weeks. This effect appeared to be more robust after the longer, kainate-induced seizures, suggesting that the heteromerization might be a function of the abnormal synchronized neuronal activity [italic]per se[/italic].
Seizures (hyperthermic and kainate-induced) in immature hippocampus lead to co-assembly of the HCN1 and HCN2 subunits, creating heteromeric channels. The modified currents encoded by these novel heteromeric channels promote the hyperexcitability of the hippocampal network observed after these seizures, and might contribute to the epileptogenic process.
[Supported by: NIH NS35439 (TZB), NS28912-S1 (ALB) and by AG00538 from the NIA to CMG.]