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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, May 11, 2005, 25(19):4844-4855; doi:10.1523/JNEUROSCI.0847-05.2005

This Article Full Text Full Text (PDF) 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 ISI Web of Science 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 ISI Web of Science (48) Citing Articles via Google Scholar Google Scholar Articles by Vitko, I. Articles by Perez-Reyes, E. Search for Related Content PubMed PubMed Citation Articles by Vitko, I. Articles by Perez-Reyes, E.

 Previous Article  |  Next Article 

Neurobiology of Disease
Functional Characterization and Neuronal Modeling of the Effects of Childhood Absence Epilepsy Variants of CACNA1H, a T-Type Calcium Channel

Iuliia Vitko,^1 * Yucai Chen,^1,2 * Juan M. Arias,¹ Yen Shen,³ Xi-Ru Wu,² and Edward Perez-Reyes¹

¹Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, ²Department of Pediatrics, First Hospital of Peking University, Beijing 100034, China, and ³National Center of Human Genome Research, Beijing 100176, China

Sequencing of the T-type Ca²⁺ channel gene CACNA1H revealed 12 nonsynonymous single nucleotide polymorphisms (SNPs) that were found only in childhood absence epilepsy (CAE) patients. One SNP, G773D, was found in two patients. The present study reports the finding of a third patient with this SNP, as well as analysis of their parents. Because of the role of T-channels in determining the intrinsic firing patterns of neurons involved in absence seizures, it was suggested that these SNPs might alter channel function. The goal of the present study was to test this hypothesis by introducing these polymorphisms into a human Ca_v3.2a cDNA and then study alterations in channel behavior using whole-cell patch-clamp recording. Eleven SNPs altered some aspect of channel gating. Computer simulations predict that seven of the SNPs would increase firing of neurons, with three of them inducing oscillations at similar frequencies, as observed during absence seizures. Three SNPs were predicted to decrease firing. Some CAE-specific SNPs (e.g., G773D) coexist with SNPs also found in controls (R788C); therefore, the effect of these polymorphisms were studied. The R788C SNP altered activity in a manner that would also lead to enhanced burst firing of neurons. The G773D-R788C combination displayed different behavior than either single SNP. Therefore, common polymorphisms can alter the effect of CAE-specific SNPs, highlighting the importance of sequence background. These results suggest that CACNA1H is a susceptibility gene that contributes to the development of polygenic disorders characterized by thalamocortical dysrhythmia, such as CAE.

Key words: calcium channels; T-type; epilepsy; single nucleotide polymorphisms; thalamus; ion channel gating

---

Received Dec 17, 2004; revised April 6, 2005; accepted April 10, 2005.

This article has been cited by other articles:

				I. I. Arias-Olguin, I. Vitko, M. Fortuna, J. P. Baumgart, S. Sokolova, I. A. Shumilin, A. Van Deusen, M. Soriano-Garcia, J. C. Gomora, and E. Perez-Reyes Characterization of the Gating Brake in the I-II Loop of Cav3.2 T-type Ca2+ Channels J. Biol. Chem., March 28, 2008; 283(13): 8136 - 8144. [Abstract] [Full Text] [PDF]

				M. T. Nelson, P. M. Joksovic, P. Su, H.-W. Kang, A. Van Deusen, J. P. Baumgart, L. S. David, T. P. Snutch, P. Q. Barrett, J.-H. Lee, et al. Molecular Mechanisms of Subtype-Specific Inhibition of Neuronal T-Type Calcium Channels by Ascorbate J. Neurosci., November 14, 2007; 27(46): 12577 - 12583. [Abstract] [Full Text] [PDF]

				M. Cataldi, V. Lariccia, V. Marzaioli, A. Cavaccini, G. Curia, D. Viggiano, L.M.T. Canzoniero, G. di Renzo, M. Avoli, and L. Annunziato Zn2+ Slows Down CaV3.3 Gating Kinetics: Implications for Thalamocortical Activity J Neurophysiol, October 1, 2007; 98(4): 2274 - 2284. [Abstract] [Full Text] [PDF]

				M. T. Nelson, J. Woo, H.-W. Kang, I. Vitko, P. Q. Barrett, E. Perez-Reyes, J.-H. Lee, H.-S. Shin, and S. M. Todorovic Reducing Agents Sensitize C-Type Nociceptors by Relieving High-Affinity Zinc Inhibition of T-Type Calcium Channels J. Neurosci., August 1, 2007; 27(31): 8250 - 8260. [Abstract] [Full Text] [PDF]

				M. E. Hildebrand, L. S. David, J. Hamid, K. Mulatz, E. Garcia, G. W. Zamponi, and T. P. Snutch Selective Inhibition of Cav3.3 T-type Calcium Channels by G{alpha}q/11-coupled Muscarinic Acetylcholine Receptors J. Biol. Chem., July 20, 2007; 282(29): 21043 - 21055. [Abstract] [Full Text] [PDF]

				I. Vitko, I. Bidaud, J. M. Arias, A. Mezghrani, P. Lory, and E. Perez-Reyes The I-II Loop Controls Plasma Membrane Expression and Gating of Cav3.2 T-Type Ca2+ Channels: A Paradigm for Childhood Absence Epilepsy Mutations J. Neurosci., January 10, 2007; 27(2): 322 - 330. [Abstract] [Full Text] [PDF]

				S.-N. Yang and P.-O. Berggren The Role of Voltage-Gated Calcium Channels in Pancreatic {beta}-Cell Physiology and Pathophysiology Endocr. Rev., October 1, 2006; 27(6): 621 - 676. [Abstract] [Full Text] [PDF]

				L. Urak, M. Feucht, N. Fathi, K. Hornik, and K. Fuchs A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity Hum. Mol. Genet., August 15, 2006; 15(16): 2533 - 2541. [Abstract] [Full Text] [PDF]

				I. Splawski, D. S. Yoo, S. C. Stotz, A. Cherry, D. E. Clapham, and M. T. Keating CACNA1H Mutations in Autism Spectrum Disorders J. Biol. Chem., August 4, 2006; 281(31): 22085 - 22091. [Abstract] [Full Text] [PDF]

				P. M. Joksovic, M. T. Nelson, V. Jevtovic-Todorovic, M. K. Patel, E. Perez-Reyes, K. P. Campbell, C.-C. Chen, and S. M. Todorovic CaV3.2 is the major molecular substrate for redox regulation of T-type Ca2+ channels in the rat and mouse thalamus J. Physiol., July 15, 2006; 574(2): 415 - 430. [Abstract] [Full Text] [PDF]

				H. Khosravani and G. W. Zamponi Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol Rev, July 1, 2006; 86(3): 941 - 966. [Abstract] [Full Text] [PDF]

				R. R. Llinas and M. Steriade Bursting of Thalamic Neurons and States of Vigilance J Neurophysiol, June 1, 2006; 95(6): 3297 - 3308. [Abstract] [Full Text] [PDF]

				X. Zhong, J. R. Liu, J. W. Kyle, D. A. Hanck, and W. S. Agnew A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies Hum. Mol. Genet., May 1, 2006; 15(9): 1497 - 1512. [Abstract] [Full Text] [PDF]

				T.D. Graves Ion channels and epilepsy QJM, April 1, 2006; 99(4): 201 - 217. [Full Text] [PDF]

				H.-J. Feng, J.-Q. Kang, L. Song, L. Dibbens, J. Mulley, and R. L. Macdonald {delta} Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of {alpha}4beta2{delta} GABAA Receptors J. Neurosci., February 1, 2006; 26(5): 1499 - 1506. [Abstract] [Full Text] [PDF]

				D. B. Halling, P. Aracena-Parks, and S. L. Hamilton Regulation of Voltage-Gated Ca2+ Channels by Calmodulin Sci. Signal., December 20, 2005; 2005(315): re15 - re15. [Abstract] [Full Text] [PDF]

				J. C. Mulley, I. E. Scheffer, L. A. Harkin, S. F. Berkovic, and L. M. Dibbens Susceptibility genes for complex epilepsy Hum. Mol. Genet., October 15, 2005; 14(suppl_2): R243 - R249. [Abstract] [Full Text] [PDF]

				J. Turnbull, H. Lohi, J. A. Kearney, G. A. Rouleau, A. V. Delgado-Escueta, M. H. Meisler, P. Cossette, and B. A. Minassian Sacred disease secrets revealed: the genetics of human epilepsy Hum. Mol. Genet., September 1, 2005; 14(17): 2491 - 2500. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help