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Gene Review

Cacnb4  -  calcium channel, voltage-dependent, beta 4...

Mus musculus

Synonyms: 3110038O15Rik, CAB4, Cacnlb4, Calcium channel voltage-dependent subunit beta 4, Cchb4, ...
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Disease relevance of Cacnb4


High impact information on Cacnb4

  • The lethargic phenotype is the first example of a mammalian neurological disease caused by an inherited defect in a non-pore-forming subunit of a voltage-gated ion channel [5].
  • Third, the candidate populations had to demonstrate GABAB receptor-mediated regulation of absence seizures in lh/lh mice; microinjections of a GABAB agonist [(-)-baclofen] and antagonist (CGP 35348) were used for this screen [6].
  • First, the neuronal populations in lh/lh mice had to have enriched GABAB binding sites compared to homologous populations in matched nonepileptic controls; baclofen-displaceable 3H-GABA binding was measured in autoradiograms for this screen [6].
  • In this study we found that anterior ventral lateral thalamic nucleus (VLa), nucleus reticularis thalami (NRT), nucleus reuniens (RE) passed all three screens, and hence are members of the neural network in which GABAB receptors regulate absence seizures in lh/lh mice [6].
  • In this report, we demonstrate that neither full-length nor truncated beta4 protein is expressed in lh/lh mice [7].

Chemical compound and disease context of Cacnb4


Biological context of Cacnb4

  • In this study, we examined the relationship between Cacnb4 and GABA(B) receptor mRNA expression in brains from Cacnb4lh homozygotes and (+/+) controls [11].
  • The maximal inhibition (Imax) value was significantly greater (80%) in lh/lh than +/+ mice, whereas the IC50 (3 microM) was unchanged [8].
  • Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(lh)) and tottering (Cacna1atg) mouse thalami [12].
  • Chronological studies of peripheral motor nerve conduction in "lethargic" mice [13].
  • The mice intraperitoneally injected with the extract became lethargic and piloerection was seen [14].

Anatomical context of Cacnb4

  • The absence of beta4 in lh/lh mice is associated with decreased expression of N-type VDCC in forebrain and cerebellum [7].
  • Synaptosomes isolated from neocortex and thalamus of age-matched male lh/lh and +/+ mice were similar in uptake of [3H]GABA [8].
  • Other effects mediated by GABAB receptors (inhibitions in Ca2+ uptake and cyclic AMP formation) were also significantly reduced in thalamic synaptosomes from lh/lh mice [8].
  • T cell function of "lethargic" mutant mice which exhibit spontaneous thymic involution was evaluated by skin transplantation and graft-versus-host reaction tests [15].
  • During the past 2 years, mutations in sodium channels, calcium channels and potassium channels have been identified by positional cloning of the spontaneous mouse mutants motor endplate disease, tottering, lethargic and weaver [16].

Associations of Cacnb4 with chemical compounds

  • CAB4 recognizes core alpha1,6 fucose regardless of terminal sugars, branching pattern, sialic acid linkage, or polylactosamine substitution [17].
  • In the thalamic preparation, the effect of baclofen (50 microM) was 58% less robust in lh/lh mice [8].
  • SCH 50911 was equipotent with the GABAB antagonist CGP 46381 (ID50 = 20 mumol/kg) in the lh/lh mouse model [9].
  • (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine hydrogen maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) antagonist (0.5 mg/kg), had no effects on SWDs and PDs in lethargic or GHB model mice [10].
  • The selective mGlu5 antagonists, MPEP, 2-methyl-6-phenylethynyl-pyridine, and SIB1893, (E)-6-methyl-2-styryl-pyridine, have been evaluated as antiepileptic drugs in DBA/2 mice and lethargic mice [18].

Enzymatic interactions of Cacnb4

  • The mouse mutant lethargic (lh) exhibits severe neurological defects due to a mutation that deletes the alpha1 subunit interaction domain of the beta4 subunit [1].

Other interactions of Cacnb4

  • A comparative analysis of channel function and neural excitability patterns in tottering, lethargic, and stargazer brain should be useful in identifying the common elements of calcium channel involvement in these absence models [19].
  • HVA peak current densities in tg and stg were increased by 22 and 45%, respectively, and a 5 mV depolarizing shift of the activation curve was observed in lh [20].
  • Since beta subunits regulate critical alpha1 subunit properties in heterologous expression systems, loss of beta4 in lethargic could dramatically alter channel localization and behavior unless beta1-3 subunits can be used as substitutes in vivo [1].
  • Two monoclonal antibodies, CAB2 and CAB4, previously raised against carbohydrate epitopes of Dictyostelium discoideum glycoproteins (Crandall, I. E. and Newell, P. C. (1989) Development 107, 87-94), specifically recognize fucose residues in alpha1,6-linkage to the asparagine-bound GlcNAc of N-linked oligosaccharides [17].
  • Glutamate decarboxylase isoforms in thalamic nuclei in lethargic mouse model of absence seizures [21].

Analytical, diagnostic and therapeutic context of Cacnb4

  • Second, the candidate populations had to generate spike-wave discharges (SWDs) during absence seizures in lh/lh mice; bipolar recording electrodes implanted into candidate neuronal structures were used in this screen [6].
  • Using the radial immunodiffusion method, it was found that serum IgG1 levels are always significantly higher in 'lethargic' mice than in their normal littermates [22].
  • We used fluorescence imaging techniques to investigate presynaptic Ca(2+) currents and neurotransmitter release at hippocampal Schaffer collateral synapses in both tottering (tg, alpha(1A) subunit) and lethargic (lh, beta(4) subunit) mutant mice [23].
  • When subjected to two-thirds partial hepatectomy, the Ctnnb1(loxp/loxp); Alb-Cre(+/-) mice were sick and lethargic, especially during the first 2-3 days only [24].


  1. beta subunit reshuffling modifies N- and P/Q-type Ca2+ channel subunit compositions in lethargic mouse brain. Burgess, D.L., Biddlecome, G.H., McDonough, S.I., Diaz, M.E., Zilinski, C.A., Bean, B.P., Campbell, K.P., Noebels, J.L. Mol. Cell. Neurosci. (1999) [Pubmed]
  2. The role of GABAB receptor activation in absence seizures of lethargic (lh/lh) mice. Hosford, D.A., Clark, S., Cao, Z., Wilson, W.A., Lin, F.H., Morrisett, R.A., Huin, A. Science (1992) [Pubmed]
  3. Paroxysmal dyskinesias in the lethargic mouse mutant. Khan, Z., Jinnah, H.A. J. Neurosci. (2002) [Pubmed]
  4. Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Matsumura, Y., Uchida, S., Kondo, Y., Miyazaki, H., Ko, S.B., Hayama, A., Morimoto, T., Liu, W., Arisawa, M., Sasaki, S., Marumo, F. Nat. Genet. (1999) [Pubmed]
  5. Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Burgess, D.L., Jones, J.M., Meisler, M.H., Noebels, J.L. Cell (1997) [Pubmed]
  6. Neural network of structures in which GABAB receptors regulate absence seizures in the lethargic (lh/lh) mouse model. Hosford, D.A., Lin, F.H., Kraemer, D.L., Cao, Z., Wang, Y., Wilson, J.T. J. Neurosci. (1995) [Pubmed]
  7. Altered expression and assembly of N-type calcium channel alpha1B and beta subunits in epileptic lethargic (lh/lh) mouse. McEnery, M.W., Copeland, T.D., Vance, C.L. J. Biol. Chem. (1998) [Pubmed]
  8. GABAB receptor-mediated effects in synaptosomes of lethargic (lh/lh) mice. Lin, F.H., Wang, Y., Lin, S., Cao, Z., Hosford, D.A. J. Neurochem. (1995) [Pubmed]
  9. Characterization of the antiabsence effects of SCH 50911, a GABA-B receptor antagonist, in the lethargic mouse, gamma-hydroxybutyrate, and pentylenetetrazole models. Hosford, D.A., Wang, Y., Liu, C.C., Snead, O.C. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  10. Pharmacological profiles of generalized absence seizures in lethargic, stargazer and gamma-hydroxybutyrate-treated model mice. Aizawa, M., Ito, Y., Fukuda, H. Neurosci. Res. (1997) [Pubmed]
  11. Age-related relationship between mRNA expression of GABA(B) receptors and calcium channel beta4 subunits in cacnb4lh mice. Lin, F., Wang, Y., Hosford, D.A. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  12. Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(lh)) and tottering (Cacna1atg) mouse thalami. Caddick, S.J., Wang, C., Fletcher, C.F., Jenkins, N.A., Copeland, N.G., Hosford, D.A. J. Neurophysiol. (1999) [Pubmed]
  13. Chronological studies of peripheral motor nerve conduction in "lethargic" mice. Herring, J.M., Dung, H.C., Yoo, J.H., Yu, J. Electromyography and clinical neurophysiology. (1981) [Pubmed]
  14. Acute toxicity of Microcystis aeruginosa and its cardiovascular effects. Oishi, S., Watanabe, M.F. Environmental research. (1986) [Pubmed]
  15. Deficiency in the thymus-dependent immunity in "lethargic" mutant mice. Dung, H.C. Transplantation (1977) [Pubmed]
  16. Ion channel mutations in mouse models of inherited neurological disease. Meisler, M.H., Sprunger, L.K., Plummer, N.W., Escayg, A., Jones, J.M. Ann. Med. (1997) [Pubmed]
  17. An IgG monoclonal antibody against Dictyostelium discoideum glycoproteins specifically recognizes Fucalpha1,6GlcNAcbeta in the core of N-linked glycans. Localized expression of core-fucosylated glycoconjugates in human tissues. Srikrishna, G., Varki, N.M., Newell, P.C., Varki, A., Freeze, H.H. J. Biol. Chem. (1997) [Pubmed]
  18. Anticonvulsant activity of two metabotropic glutamate group I antagonists selective for the mGlu5 receptor: 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and (E)-6-methyl-2-styryl-pyridine (SIB 1893). Chapman, A.G., Nanan, K., Williams, M., Meldrum, B.S. Neuropharmacology (2000) [Pubmed]
  19. Single gene defects in mice: the role of voltage-dependent calcium channels in absence models. Burgess, D.L., Noebels, J.L. Epilepsy Res. (1999) [Pubmed]
  20. Mutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons. Zhang, Y., Mori, M., Burgess, D.L., Noebels, J.L. J. Neurosci. (2002) [Pubmed]
  21. Glutamate decarboxylase isoforms in thalamic nuclei in lethargic mouse model of absence seizures. Lin, F.H., Lin, S., Wang, Y., Hosford, D.A. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  22. A study of the increased serum level of IgG1 in 'lethargic' mice combined with a depressed thymus-dependent lymphoid system. Dung, H.C., Lawson, R.L., Stevens, M. J. Immunogenet. (1977) [Pubmed]
  23. Presynaptic Ca(2+) influx at a mouse central synapse with Ca(2+) channel subunit mutations. Qian, J., Noebels, J.L. J. Neurosci. (2000) [Pubmed]
  24. Conditional Deletion of beta-Catenin Reveals Its Role in Liver Growth and Regeneration. Tan, X., Behari, J., Cieply, B., Michalopoulos, G.K., Monga, S.P. Gastroenterology (2006) [Pubmed]
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