Gene Symbol: Cacnb4
Description: calcium channel, voltage-dependent, beta 4 subunit
Alias: 3110038O15Rik, Cchb4, voltage-dependent L-type calcium channel subunit beta-4, CAB4, calcium channel voltage-dependent subunit beta 4
Species: mouse
Products:     Cacnb4

Top Publications

  1. Subramanyam P, Obermair G, Baumgartner S, Gebhart M, Striessnig J, Kaufmann W, et al. Activity and calcium regulate nuclear targeting of the calcium channel beta4b subunit in nerve and muscle cells. Channels (Austin). 2009;3:343-55 pubmed
    ..The activity-dependent shuttling of beta(4b) into and out of the nucleus indicates a specific role of this beta subunit in neurons, in communicating the activity of calcium channels to the nucleus. ..
  2. Wakana S, Sugaya E, Naramoto F, Yokote N, Maruyama C, Jin W, et al. Gene mapping of SEZ group genes and determination of pentylenetetrazol susceptible quantitative trait loci in the mouse chromosome. Brain Res. 2000;857:286-90 pubmed
    ..Since epilepsy is assumed to be a disease syndrome which is probably manifested by abnormal expression of multifocal genes, determination of the role of each chromosomal locus in the provocation of seizure activity is important. ..
  3. Lin F, Wang Y, Hosford D. Age-related relationship between mRNA expression of GABA(B) receptors and calcium channel beta4 subunits in cacnb4lh mice. Brain Res Mol Brain Res. 1999;71:131-5 pubmed
    ..In this study, we examined the relationship between Cacnb4 and GABA(B) receptor mRNA expression in brains from Cacnb4lh homozygotes and (+/+) controls...
  4. Leikauf G, Concel V, Liu P, Bein K, Berndt A, Ganguly K, et al. Haplotype association mapping of acute lung injury in mice implicates activin a receptor, type 1. Am J Respir Crit Care Med. 2011;183:1499-509 pubmed publisher
    ..5-fold. Associations were identified on chromosomes 1, 2, 4, 11, and 12. Seven genes (Acvr1, Cacnb4, Ccdc148, Galnt13, Rfwd2, Rpap2, and Tgfbr3) had single nucleotide polymorphism (SNP) associations within the gene...
  5. Devanagondi R, Egami K, Ledoux M, Hess E, Jinnah H. Neuroanatomical substrates for paroxysmal dyskinesia in lethargic mice. Neurobiol Dis. 2007;27:249-57 pubmed
    ..Surgical removal of the cerebellum worsened ataxia but eliminated paroxysmal dyskinesias. These studies support the hypothesis that abnormal cerebellar output contributes to paroxysmal dyskinesias. ..
  6. Aizawa M, Ito Y, Fukuda H. Pharmacological profiles of generalized absence seizures in lethargic, stargazer and gamma-hydroxybutyrate-treated model mice. Neurosci Res. 1997;29:17-25 pubmed
    ..These results suggest that GABAB receptors play a significant role in the pathogenesis of generalized absence seizures in these models, although the mechanism involved in stargazer mice differ from that in the other two. ..
  7. Burgess D, Jones J, Meisler M, Noebels J. Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell. 1997;88:385-92 pubmed determine that the ataxia and seizures in the lethargic (lh) mouse arise from mutation of the beta-subunit gene Cchb4 on mouse chromosome 2...
  8. Caddick S, Wang C, Fletcher C, Jenkins N, Copeland N, Hosford D. Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(lh)) and tottering (Cacna1atg) mouse thalami. J Neurophysiol. 1999;81:2066-74 pubmed
    Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(lh)) and tottering (Cacna1atg) mouse thalami...
  9. Ball S, Powers P, Shin H, Morgans C, Peachey N, Gregg R. Role of the beta(2) subunit of voltage-dependent calcium channels in the retinal outer plexiform layer. Invest Ophthalmol Vis Sci. 2002;43:1595-603 pubmed
    ..The expression of both of these subunits is required for normal maintenance and/or formation of the OPL and synaptic transmission. ..

More Information


  1. Obermair G, Schlick B, Di Biase V, Subramanyam P, Gebhart M, Baumgartner S, et al. Reciprocal interactions regulate targeting of calcium channel beta subunits and membrane expression of alpha1 subunits in cultured hippocampal neurons. J Biol Chem. 2010;285:5776-91 pubmed publisher
  2. Fletcher C, Frankel W. Ataxic mouse mutants and molecular mechanisms of absence epilepsy. Hum Mol Genet. 1999;8:1907-12 pubmed
    ..Then, from the new wave of genetic and functional studies of these mutants we discuss their prospects for yielding insight into the molecular mechanisms of epilepsy. ..
  3. Tadmouri A, Kiyonaka S, Barbado M, Rousset M, Fablet K, Sawamura S, et al. Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy. EMBO J. 2012;31:3730-44 pubmed publisher
    ..Here, we describe a novel signalling pathway in which the VGCC Cacnb4 subunit directly couples neuronal excitability to transcription...
  4. Schlick B, Flucher B, Obermair G. Voltage-activated calcium channel expression profiles in mouse brain and cultured hippocampal neurons. Neuroscience. 2010;167:786-98 pubmed publisher
    ..Developmental changes are likely determined by an intrinsic program and not regulated by changes in neuronal activity. ..
  5. Burgess D, Biddlecome G, McDonough S, Diaz M, Zilinski C, Bean B, et al. beta subunit reshuffling modifies N- and P/Q-type Ca2+ channel subunit compositions in lethargic mouse brain. Mol Cell Neurosci. 1999;13:293-311 pubmed
    ..The existence of beta subunit reshuffling demonstrates that molecular plasticity of Ca2+ channel assembly, a normal feature of early brain development, is retained in the mature brain. ..
  6. Qian J, Noebels J. Presynaptic Ca(2+) influx at a mouse central synapse with Ca(2+) channel subunit mutations. J Neurosci. 2000;20:163-70 pubmed
    ..The present study reveals compensatory molecular mechanisms in the regulation of presynaptic Ca(2+) entry and neurotransmitter release. ..
  7. Lin F, Lin S, Wang Y, Hosford D. Glutamate decarboxylase isoforms in thalamic nuclei in lethargic mouse model of absence seizures. Brain Res Mol Brain Res. 1999;71:127-30 pubmed
    ..These data suggest that GABA-synthesis is maintained or increased in NRT neurons in the Cacnb4lh mouse model. ..
  8. Dung H. Deficiency in the thymus-dependent immunity in "lethargic" mutant mice. Transplantation. 1977;23:39-43 pubmed
    ..Implications of these results in understanding the immunological status of lethargic mice were considered. ..
  9. Song I, Kim D, Choi S, Sun M, Kim Y, Shin H. Role of the alpha1G T-type calcium channel in spontaneous absence seizures in mutant mice. J Neurosci. 2004;24:5249-57 pubmed
  10. Marmorstein L, Wu J, McLaughlin P, Yocom J, Karl M, Neussert R, et al. The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1). J Gen Physiol. 2006;127:577-89 pubmed
    ..Furthermore, we suggest that the loss of vision associated with BMD is not caused by the same pathologic process as the diminished LP, but rather is caused by as yet unidentified effects of best-1 on other cellular processes. ..
  11. Meisler M, Sprunger L, Plummer N, Escayg A, Jones J. Ion channel mutations in mouse models of inherited neurological disease. Ann Med. 1997;29:569-74 pubmed
    ..The mouse studies indicate that mutations in ion channel genes are likely to be responsible for a broad spectrum of clinical phenotypes in human neurological disorders. ..
  12. Badou A, Jha M, Matza D, Mehal W, Freichel M, Flockerzi V, et al. Critical role for the beta regulatory subunits of Cav channels in T lymphocyte function. Proc Natl Acad Sci U S A. 2006;103:15529-34 pubmed
    ..These observations suggest that the Cav channels expressed by T cells have adopted novel regulation/gating mechanisms. ..
  13. Ferrándiz Huertas C, Gil Mínguez M, Lujan R. Regional expression and subcellular localization of the voltage-gated calcium channel ? subunits in the developing mouse brain. J Neurochem. 2012;122:1095-107 pubmed publisher
    ..These results shed new light on the developmental regulation and subcellular localization of Ca(v) ? subunits, and their possible role in pre- and post-synaptic transmission. ..
  14. Hosford D, Clark S, Cao Z, Wilson W, Lin F, Morrisett R, et al. The role of GABAB receptor activation in absence seizures of lethargic (lh/lh) mice. Science. 1992;257:398-401 pubmed
    ..Therefore, enhanced GABAB receptor-mediated synaptic responses may underlie absence seizures in lh/lh mice, and GABAB receptor antagonists hold promise as anticonvulsants for absence seizures. ..
  15. Hosford D, Lin F, Kraemer D, Cao Z, Wang Y, Wilson J. Neural network of structures in which GABAB receptors regulate absence seizures in the lethargic (lh/lh) mouse model. J Neurosci. 1995;15:7367-76 pubmed
  16. Etemad S, Campiglio M, Obermair G, Flucher B. The juvenile myoclonic epilepsy mutant of the calcium channel ?(4) subunit displays normal nuclear targeting in nerve and muscle cells. Channels (Austin). 2014;8:334-43 pubmed
    ..Mutations of the calcium channel ?(4) subunit gene (CACNB4) cause juvenile myoclonic epilepsy in humans and ataxia and epileptic seizures in mice...
  17. Beguin P, Nagashima K, Mahalakshmi R, Vigot R, Matsunaga A, Miki T, et al. BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis. J Cell Biol. 2014;205:233-49 pubmed publisher
    ..Thus, BARP can modulate the localization of Cav? and its association with the Cav?1 subunit to negatively regulate VGCC activity. ..
  18. Caddick S, Hosford D. The role of GABAB mechanisms in animal models of absence seizures. Mol Neurobiol. 1996;13:23-32 pubmed
    ..The current evidence and interpretations of this work are presented here. ..
  19. Kaja S, Todorov B, van de Ven R, Ferrari M, Frants R, van den Maagdenberg A, et al. Redundancy of Cav2.1 channel accessory subunits in transmitter release at the mouse neuromuscular junction. Brain Res. 2007;1143:92-101 pubmed
    ..1 channel function due to alpha(2)delta-2 absence. We conclude that alpha(2)delta-2, beta(4), and gamma(2) accessory subunits are redundant for the transmitter release-mediating function of presynaptic Ca(v)2.1 channels at the mouse NMJ. ..
  20. Etemad S, Obermair G, Bindreither D, Benedetti A, Stanika R, Di Biase V, et al. Differential neuronal targeting of a new and two known calcium channel ?4 subunit splice variants correlates with their regulation of gene expression. J Neurosci. 2014;34:1446-61 pubmed publisher
  21. Betz R, Leibiger B, Farnebo F, Lagercrantz S, Piehl F, Leibiger I, et al. Mapping of the human Ca2+ channel beta 4 subunit to 2q22-23 and its expression in developing mouse. Mamm Genome. 1998;9:310-1 pubmed
  22. Murakami M, Suzuki T, Wu T, Kuwasako K, Takahashi E, Watanabe H, et al. Modified autonomic regulation in mice mutated in the β4 subunit of the lh/lh calcium channel. Biochem Biophys Res Commun. 2015;461:200-5 pubmed publisher
    ..Thus, our present study revealed that the β4 subunit played a significant role in regulation of sympathetic and parasympathetic nerve activities. ..
  23. Khan Z, Jinnah H. Paroxysmal dyskinesias in the lethargic mouse mutant. J Neurosci. 2002;22:8193-200 pubmed
    Lethargic mutant mice carry a mutation in the CCHB4 gene, which encodes the beta4 subunit of voltage-regulated calcium channels...
  24. Dung H, Swigart R. Histo-pathologic observations of the nervous and lymphoid tissues of "lethargic" mutant mice. Tex Rep Biol Med. 1972;30:23-39 pubmed
  25. Herring J, Dung H, Yoo J, Yu J. Chronological studies of peripheral motor nerve conduction in "lethargic" mice. Electromyogr Clin Neurophysiol. 1981;21:121-34 pubmed
  26. Meisler M, Kearney J, Ottman R, Escayg A. Identification of epilepsy genes in human and mouse. Annu Rev Genet. 2001;35:567-88 pubmed
    ..The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies. ..
  27. Bodrikov V, Sytnyk V, Leshchyns ka I, den Hertog J, Schachner M. NCAM induces CaMKIIalpha-mediated RPTPalpha phosphorylation to enhance its catalytic activity and neurite outgrowth. J Cell Biol. 2008;182:1185-200 pubmed publisher
    ..Thus, we reveal a novel function for a cell adhesion molecule in coordination of cell behavior with intracellular phosphatase activity. ..
  28. Zhang Y, Mori M, Burgess D, Noebels J. Mutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons. J Neurosci. 2002;22:6362-71 pubmed
    ..These alterations increase the probability for abnormal thalamocortical synchronization and absence epilepsy in tg, lh, and stg mice. ..
  29. Escayg A, Jones J, Kearney J, Hitchcock P, Meisler M. Calcium channel beta 4 (CACNB4): human ortholog of the mouse epilepsy gene lethargic. Genomics. 1998;50:14-22 pubmed human neurological disease, we determined the chromosomal location and intron/exon structure of the human CACNB4 gene...
  30. Freise D, Himmerkus N, Schroth G, Trost C, Weissgerber P, Freichel M, et al. Mutations of calcium channel beta subunit genes in mice. Biol Chem. 1999;380:897-902 pubmed
    ..Here we summarize the phenotype of mice deficient in the beta1 subunit, the beta3 subunit or the beta4 subunit, respectively. ..
  31. Chin H, Kwon O, Jung H, Kim D, Kozak C. Genetic mapping of the mouse genes encoding the voltage-sensitive calcium channel subunits. Genomics. 1995;28:592-5 pubmed
    ..The alpha 1, beta 2, and beta 4 subunit genes, termed Cchna1, Cchb2, and Cchb4, are located at different sites on proximal Chr 2, while the beta 3 subunit gene Cchb3 maps to Chr 15 near Wnt1...
  32. Barclay J, Rees M. Mouse models of spike-wave epilepsy. Epilepsia. 1999;40 Suppl 3:17-22 pubmed
    ..The question this raises as to the validity of these models for human spike-wave epilepsy is considered. Finally, the effect these discoveries will have on the understanding and treatment of human spike-wave epilepsy are discussed. ..
  33. McEnery M, Copeland T, Vance C. Altered expression and assembly of N-type calcium channel alpha1B and beta subunits in epileptic lethargic (lh/lh) mouse. J Biol Chem. 1998;273:21435-8 pubmed
    ..It is intriguing to speculate that the increased excitability and susceptibility to seizures observed in the lh/lh mouse arises from the inappropriate expression of an immature population of N-type VDCC throughout neuronal development. ..
  34. Puranam R, McNamara J. Seizure disorders in mutant mice: relevance to human epilepsies. Curr Opin Neurobiol. 1999;9:281-7 pubmed
  35. Berger R, Theodor L, Shoham J, Gokkel E, Brok Simoni F, Avraham K, et al. The characterization and localization of the mouse thymopoietin/lamina-associated polypeptide 2 gene and its alternatively spliced products. Genome Res. 1996;6:361-70 pubmed
    ..These findings suggest that there may be more human transcripts than currently recognized. The possible involvement of the new growing family of Tmpo proteins in nuclear architecture and cell cycle control is discussed. ..
  36. Kuhn S, Knirsch M, Ruttiger L, Kasperek S, Winter H, Freichel M, et al. Ba2+ currents in inner and outer hair cells of mice lacking the voltage-dependent Ca2+ channel subunits beta3 or beta4. Channels (Austin). 2009;3:366-76 pubmed
    ..These results indicate that neither Ca(V)beta3 nor Ca(V)beta4 are indispensable for hair cell Ca(2+) currents but contribute to the overall current properties. ..
  37. Billings S, Clarke G, Nishimune H. ELKS1 and Ca(2+) channel subunit ?4 interact and colocalize at cerebellar synapses. Neuroreport. 2012;23:49-54 pubmed publisher
    ..These results demonstrate that these two proteins interact in vitro and colocalize in the cerebellum, and suggest that their interaction may play a role at the molecular layer synapses of the cerebellum. ..
  38. Dung H, Lawson R, Stevens M. A study of the increased serum level of IgG1 in 'lethargic' mice combined with a depressed thymus-dependent lymphoid system. J Immunogenet. 1977;4:287-93 pubmed
    ..The authors note the similarities of other mouse mutations to that of the 'lethargic' mouse and propose the possibility that a common mechanism may account for immunologic deficiencies in several types of mutant mice. ..
  39. Acosta L, Haase H, Morano I, Moorman A, Franco D. Regional expression of L-type calcium channel subunits during cardiac development. Dev Dyn. 2004;230:131-6 pubmed
    ..These findings suggest that beta subunits might play a major role in conferring calcium handling heterogeneity within the developing embryonic myocardium, while alpha1C subunits might contribute just transiently. ..
  40. Murakami M, Miyoshi I, Suzuki T, Sasano H, Iijima T. Structures of the murine genes for the beta1- and beta4-subunits of the voltage-dependent calcium channel. J Mol Neurosci. 2003;21:13-21 pubmed
    ..Furthermore, mRNA of these beta-subunits is strongly expressed in dorsal root ganglion neurons, which have many voltage-dependent calcium channels. ..
  41. Burgess D, Noebels J. Single gene defects in mice: the role of voltage-dependent calcium channels in absence models. Epilepsy Res. 1999;36:111-22 pubmed locus encodes the calcium channel alpha1 subunit gene Cacna1a, lethargic (lh) encodes the beta subunit gene Cacnb4, and stargazer (stg) encodes the gamma subunit gene Cacng2...
  42. Lin F, Cao Z, Hosford D. Increased number of GABAB receptors in the lethargic (lh/lh) mouse model of absence epilepsy. Brain Res. 1993;608:101-6 pubmed
    ..Together with evidence that GABAB receptor activation can produce disinhibition, our data support a role for GABAB receptors in the expression of absence seizures in lh/lh mice. ..
  43. Castillo S, Xiao Q, Lyu M, Kozak C, Nikodem V. Organization, sequence, chromosomal localization, and promoter identification of the mouse orphan nuclear receptor Nurr1 gene. Genomics. 1997;41:250-7 pubmed
    ..These data help to explain the different response characteristics of two closely related early response genes, Nurr1 and Nur77. ..
  44. Ishige K, Ito Y, Fukuda H. Characterization of absence seizure-dependent cyclic AMP responsive element-and activator protein 1 DNA-binding activities in lethargic (lh/lh) mice. Neurosci Lett. 1999;262:53-6 pubmed
    ..These results suggest that enhanced nuclear CRE- and AP-1 DNA-binding activities in the thalamocortical region are related to generation and/or propagation of absence seizures in lethargic mice. ..
  45. Benedetti B, Benedetti A, Flucher B. Loss of the calcium channel ?4 subunit impairs parallel fibre volley and Purkinje cell firing in cerebellum of adult ataxic mice. Eur J Neurosci. 2016;43:1486-98 pubmed publisher
  46. Hosford D, Wang Y, Liu C, Snead O. Characterization of the antiabsence effects of SCH 50911, a GABA-B receptor antagonist, in the lethargic mouse, gamma-hydroxybutyrate, and pentylenetetrazole models. J Pharmacol Exp Ther. 1995;274:1399-403 pubmed
    ..These findings suggest that antiabsence activity may be a defining feature of GABAB receptor antagonists and provide a rationale for pursuing clinical trials of GABAB receptor antagonists in human patients with absence seizures. ..
  47. Lin F, Wang Y, Lin S, Cao Z, Hosford D. GABAB receptor-mediated effects in synaptosomes of lethargic (lh/lh) mice. J Neurochem. 1995;65:2087-95 pubmed
    ..It is possible that selective effects of presynaptic GABAB receptors or GABA release in neocortex and thalamic nuclei of lh/lh mice may contribute to mechanisms underlying absence seizures. ..
  48. Kozak C, Sangameswaran L. Genetic mapping of the peripheral sodium channel genes, Scn9a and Scn10a, in the mouse. Mamm Genome. 1996;7:787-8 pubmed
  49. Tardiff J, Krauter K. Divergent expression of alpha1-protease inhibitor genes in mouse and human. Nucleic Acids Res. 1998;26:3794-9 pubmed
    ..This difference between the species appears to result from an absence of a functional macrophage-specific promoter in mice. ..
  50. Batista Brito R, Machold R, Klein C, Fishell G. Gene expression in cortical interneuron precursors is prescient of their mature function. Cereb Cortex. 2008;18:2306-17 pubmed publisher
    ..Moreover, our work has revealed that many of the genes expressed in cortical interneuron precursors have been independently linked to neurological disorders in both mice and humans. ..
  51. Xu X, Lee Y, Holm J, Terry M, Oswald R, Horne W. The Ca2+ channel beta4c subunit interacts with heterochromatin protein 1 via a PXVXL binding motif. J Biol Chem. 2011;286:9677-87 pubmed publisher
    ..An NMR-based two-site docking model of ?4c in complex with dimerized CSD is presented. Possible roles for the interaction are discussed. ..
  52. Lin F, Barun S, Lutz C, Wang Y, Hosford D. Decreased (45)Ca(2)(+) uptake in P/Q-type calcium channels in homozygous lethargic (Cacnb4lh) mice is associated with increased beta3 and decreased beta4 calcium channel subunit mRNA expression. Brain Res Mol Brain Res. 1999;71:1-10 pubmed
    ..Together, these findings indicate that a host of changes in VGCC subunit composition accompany reduced function of P/Q-type channels in homozygous lethargic mice. ..
  53. Cope D, Di Giovanni G, Fyson S, Orbán G, Errington A, Lorincz M, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15:1392-8 pubmed publisher
    ..These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic importance and highlight potential therapeutic targets for the treatment of absence epilepsy. ..
  54. Link S, Meissner M, Held B, Beck A, Weissgerber P, Freichel M, et al. Diversity and developmental expression of L-type calcium channel beta2 proteins and their influence on calcium current in murine heart. J Biol Chem. 2009;284:30129-37 pubmed publisher
  55. Guillaume D, Grisar T, Vergniolle Burette M. Glial contribution to seizure: carbonic anhydrase activity in epileptic mammalian brain. Epilepsia. 1991;32:10-5 pubmed
    ..The hypothesis of an adaptive glial mechanism, relating to the age-dependent decrease of seizure susceptibility in DBA/2 mice, is postulated. ..