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Gene Review

Cacng2  -  calcium channel, voltage-dependent, gamma...

Mus musculus

Synonyms: AW060990, B230105C07Rik, B930041E13Rik, Neuronal voltage-gated calcium channel gamma-2 subunit, Stargazin, ...
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Disease relevance of Cacng2


High impact information on Cacng2

  • Stargazer mice have spike-wave seizures characteristic of absence epilepsy, with accompanying defects in the cerebellum and inner ear [5].
  • The anticipated effect in stargazer mutants, inappropriate Ca2+ entry, may contribute to their more pronounced seizure phenotype compared with other mouse absence models with Ca2+-channel defects [5].
  • It encodes a 36-kD protein (stargazin) with structural similarity to the gamma subunit of skeletal muscle voltage-gated calcium (Ca2+) channels [5].
  • Stargazin is brain-specific and, like other neuronal Ca2+-channel subunits, is enriched in synaptic plasma membranes [5].
  • In vitro, stargazin increases steady-state inactivation of alpha1 class A Ca2+ channels [5].

Chemical compound and disease context of Cacng2


Biological context of Cacng2

  • All three mutations affect the Cacng2 mRNA levels as they all arise from disruptions within the introns of this gene [8].
  • Absence of cerebellar granule cell BDNF mRNA in stg/stg mice demonstrates that sustained expression of this neurotrophin is not required for cell survival in the developing cerebellar cortex [9].
  • The data suggest that the cell adhesion function of stargazin preceded its current role in neurons as a regulator of either voltage-dependent calcium channels or AMPA receptors [10].
  • Here, we report that expression of stargazin in mouse L-fibroblasts results in cell aggregation comparable with that produced by claudins, and present evidence that the interaction is heterotypic and calcium dependent [10].
  • Intracellular and whole cell recordings from stg/stg neurons in deep layers showed spontaneous giant depolarizing excitatory post-synaptic potentials generating bursts of action potentials, and a 78% reduction in the afterburst hyperpolarization [11].

Anatomical context of Cacng2


Associations of Cacng2 with chemical compounds

  • We established that the alpha4 betagamma2 subunit-containing, flunitrazepam-insensitive subtype of GABARs, not normally a significant GABAR in DG neurons, was strongly upregulated in stg DG, apparently arising at the expense of extrasynaptic alpha4 betadelta-containing receptors [12].
  • Functional studies suggest a dual role for stargazin, both as a modulatory gamma subunit for voltage-dependent calcium channels and as a regulator of post-synaptic membrane targeting for alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors [10].
  • The sensitivity of stg mutant GCs to exogenously applied AMPA was greatly reduced, whereas that to NMDA was unchanged [3].
  • However, it is unclear whether the trafficking of kainate receptors, which are structurally very similar to AMPA receptors, is also dependent on stargazin [15].
  • Cerebellar Golgi, Purkinje, and basket cells have reduced gamma-aminobutyric acid immunoreactivity in stargazer mutant mice [16].

Regulatory relationships of Cacng2

  • Genetic analysis of stargazer mice determined that the defective gene encodes a protein expressed in brain (gamma2) with limited homology to the skeletal muscle L-type calcium channel gamma1 subunit [17].

Other interactions of Cacng2


Analytical, diagnostic and therapeutic context of Cacng2


  1. A targeted mutation in Cacng4 exacerbates spike-wave seizures in stargazer (Cacng2) mice. Letts, V.A., Mahaffey, C.L., Beyer, B., Frankel, W.N. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Stargazer: a new neurological mutant on chromosome 15 in the mouse with prolonged cortical seizures. Noebels, J.L., Qiao, X., Bronson, R.T., Spencer, C., Davisson, M.T. Epilepsy Res. (1990) [Pubmed]
  3. Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. Hashimoto, K., Fukaya, M., Qiao, X., Sakimura, K., Watanabe, M., Kano, M. J. Neurosci. (1999) [Pubmed]
  4. USH3A transcripts encode clarin-1, a four-transmembrane-domain protein with a possible role in sensory synapses. Adato, A., Vreugde, S., Joensuu, T., Avidan, N., Hamalainen, R., Belenkiy, O., Olender, T., Bonne-Tamir, B., Ben-Asher, E., Espinos, C., Millán, J.M., Lehesjoki, A.E., Flannery, J.G., Avraham, K.B., Pietrokovski, S., Sankila, E.M., Beckmann, J.S., Lancet, D. Eur. J. Hum. Genet. (2002) [Pubmed]
  5. The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Letts, V.A., Felix, R., Biddlecome, G.H., Arikkath, J., Mahaffey, C.L., Valenzuela, A., Bartlett, F.S., Mori, Y., Campbell, K.P., Frankel, W.N. Nat. Genet. (1998) [Pubmed]
  6. 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]
  7. Stargazer-a mouse to seize! Letts, V.A. Epilepsy currents / American Epilepsy Society. (2005) [Pubmed]
  8. Phenotypic heterogeneity in the stargazin allelic series. Letts, V.A., Kang, M.G., Mahaffey, C.L., Beyer, B., Tenbrink, H., Campbell, K.P., Frankel, W.N. Mamm. Genome (2003) [Pubmed]
  9. Selective failure of brain-derived neurotrophic factor mRNA expression in the cerebellum of stargazer, a mutant mouse with ataxia. Qiao, X., Hefti, F., Knusel, B., Noebels, J.L. J. Neurosci. (1996) [Pubmed]
  10. The alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor trafficking regulator "stargazin" is related to the claudin family of proteins by Its ability to mediate cell-cell adhesion. Price, M.G., Davis, C.F., Deng, F., Burgess, D.L. J. Biol. Chem. (2005) [Pubmed]
  11. Increased excitability and inward rectification in layer V cortical pyramidal neurons in the epileptic mutant mouse Stargazer. Di Pasquale, E., Keegan, K.D., Noebels, J.L. J. Neurophysiol. (1997) [Pubmed]
  12. Aberrant GABA(A) receptor expression in the dentate gyrus of the epileptic mutant mouse stargazer. Payne, H.L., Donoghue, P.S., Connelly, W.M., Hinterreiter, S., Tiwari, P., Ives, J.H., Hann, V., Sieghart, W., Lees, G., Thompson, C.L. J. Neurosci. (2006) [Pubmed]
  13. Stargazin mutation impairs cerebellar synaptogenesis, synaptic maturation and synaptic protein distribution. Meng, H., Walker, N., Su, Y., Qiao, X. Brain Res. (2006) [Pubmed]
  14. Decreased expression of GABAA receptor alpha6 and beta3 subunits in stargazer mutant mice: a possible role for brain-derived neurotrophic factor in the regulation of cerebellar GABAA receptor expression? Thompson, C.L., Tehrani, M.H., Barnes, E.M., Stephenson, F.A. Brain Res. Mol. Brain Res. (1998) [Pubmed]
  15. Stargazin differentially controls the trafficking of alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate and kainate receptors. Chen, L., El-Husseini, A., Tomita, S., Bredt, D.S., Nicoll, R.A. Mol. Pharmacol. (2003) [Pubmed]
  16. Cerebellar Golgi, Purkinje, and basket cells have reduced gamma-aminobutyric acid immunoreactivity in stargazer mutant mice. Richardson, C.A., Leitch, B. J. Comp. Neurol. (2002) [Pubmed]
  17. Biochemical and anatomical evidence for specialized voltage-dependent calcium channel gamma isoform expression in the epileptic and ataxic mouse, stargazer. Sharp, A.H., Black, J.L., Dubel, S.J., Sundarraj, S., Shen, J.P., Yunker, A.M., Copeland, T.D., McEnery, M.W. Neuroscience (2001) [Pubmed]
  18. Phenotype of cerebellar glutamatergic neurons is altered in stargazer mutant mice lacking brain-derived neurotrophic factor mRNA expression. Richardson, C.A., Leitch, B. J. Comp. Neurol. (2005) [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. Microtubule-associated protein light chain 2 is a stargazin-AMPA receptor complex-interacting protein in vivo. Ives, J.H., Fung, S., Tiwari, P., Payne, H.L., Thompson, C.L. J. Biol. Chem. (2004) [Pubmed]
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