QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 14, 2009, 29(2):371-380; doi:10.1523/JNEUROSCI.5295-08.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Powell, K. L. Articles by O'Brien, T. J. Search for Related Content PubMed PubMed Citation Articles by Powell, K. L. Articles by O'Brien, T. J.

 Previous Article  |  Next Article 

Neurobiology of Disease
A Ca_v3.2 T-Type Calcium Channel Point Mutation Has Splice-Variant-Specific Effects on Function and Segregates with Seizure Expression in a Polygenic Rat Model of Absence Epilepsy

Kim L. Powell,^1 * Stuart M. Cain,^2 * Caroline Ng,¹ Shreerang Sirdesai,¹ Laurence S. David,² Mervyn Kyi,¹ Esperanza Garcia,² John R. Tyson,² Christopher A. Reid,³ Melanie Bahlo,⁴ Simon J. Foote,⁵ Terrance P. Snutch,² and Terence J. O'Brien¹

¹Departments of Medicine, Surgery, and Neurology, The Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria 3050, Australia, ²Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4, ³Howard Florey Institute, University of Melbourne, Melbourne, Victoria 3010, Australia, ⁴The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia, and ⁵Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7000, Australia

Correspondence should be addressed to either of the following: Terence O'Brien, Department of Medicine (Royal Melbourne Hospital/Western Hospital), The University of Melbourne, 4th Floor, Clinical Sciences Building, Royal Melbourne Hospital, Royal Parade, Parkville, Victoria 3050, Australia, Email: obrientj{at}unimelb.edu.au; or Terrance Snutch, Michael Smith Laboratories, The University of British Columbia, 301-2185 East Mall, Vancouver, British Columbia, Canada V6T 1Z4, Email: snutch{at}msl.ubc.ca

Low-voltage-activated, or T-type, calcium (Ca²⁺) channels are believed to play an essential role in the generation of absence seizures in the idiopathic generalized epilepsies (IGEs). We describe a homozygous, missense, single nucleotide (G to C) mutation in the Ca_v3.2 T-type Ca²⁺ channel gene (Cacna1h) in the genetic absence epilepsy rats from Strasbourg (GAERS) model of IGE. The GAERS Ca_v3.2 mutation (gcm) produces an arginine to proline (R1584P) substitution in exon 24 of Cacna1h, encoding a portion of the III–IV linker region in Ca_v3.2. gcm segregates codominantly with the number of seizures and time in seizure activity in progeny of an F1 intercross. We have further identified two major thalamic Cacna1h splice variants, either with or without exon 25. gcm introduced into the splice variants acts "epistatically," requiring the presence of exon 25 to produce significantly faster recovery from channel inactivation and greater charge transference during high-frequency bursts. This gain-of-function mutation, the first reported in the GAERS polygenic animal model, has a novel mechanism of action, being dependent on exonic splicing for its functional consequences to be expressed.

Key words: idiopathic generalized epilepsy; absence seizures; T-type calcium channel; splice variant; point mutation; genetic absence epilepsy rats from Strasbourg; GAERS

---

Received Nov. 3, 2008; accepted Nov. 20, 2008.

Correspondence should be addressed to either of the following: Terence O'Brien, Department of Medicine (Royal Melbourne Hospital/Western Hospital), The University of Melbourne, 4th Floor, Clinical Sciences Building, Royal Melbourne Hospital, Royal Parade, Parkville, Victoria 3050, Australia, Email: obrientj{at}unimelb.edu.au; or Terrance Snutch, Michael Smith Laboratories, The University of British Columbia, 301-2185 East Mall, Vancouver, British Columbia, Canada V6T 1Z4, Email: snutch{at}msl.ubc.ca

This article has been cited by other articles:

				E. Perez-Reyes G Protein-Mediated Inhibition of Cav3.2 T-Type Channels Revisited Mol. Pharmacol., February 1, 2010; 77(2): 136 - 138. [Abstract] [Full Text] [PDF]

				F. M. Dreyfus, A. Tscherter, A. C. Errington, J. J. Renger, H.-S. Shin, V. N. Uebele, V. Crunelli, R. C. Lambert, and N. Leresche Selective T-Type Calcium Channel Block in Thalamic Neurons Reveals Channel Redundancy and Physiological Impact of ITwindow J. Neurosci., January 6, 2010; 30(1): 99 - 109. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help