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Cacna1a  -  calcium channel, voltage-dependent, P/Q...

Mus musculus

Synonyms: APCA, BI, Brain calcium channel I, Caca1a, Cach4, ...
 
 
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Disease relevance of Cacna1a

  • A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression [1].
  • It has been well established that mice with a mutation at Cacna1a such as tottering and leaner show absence seizures [2].
  • Mice carrying mutations of the gene encoding the ion pore of the P/Q calcium channel (Cacna1a) are an instance in which cerebellar dysfunction may be attributable to altered electrophysiology and thus provide an opportunity to study how neuronal intrinsic properties dictate signal processing in the ocular motor system [3].
  • Mutations of the alpha1A calcium channel subunit have been shown to cause such human neurological diseases as familial hemiplegic migraine, episodic ataxia-2, and spinocerebellar ataxia 6 and also to cause the murine neurological phenotypes of tottering and leaner [4].
  • All the proteins are unrelated outside of the polyglutamine stretch and most are novel with exception of the androgen receptor and the voltage gated alpha 1A calcium channel, which are mutated in spinal and bulbar muscular atrophy and spinocerebellar ataxia type 6 [5].
 

High impact information on Cacna1a

  • Mutations at the mouse tottering (tg) locus cause a delayed-onset, recessive neurological disorder resulting in ataxia, motor seizures, and behavioral absence seizures resembling petit mal epilepsy in humans [6].
  • The alpha1A gene is widely expressed in the central nervous system with prominent, uniform expression in the cerebellum. alpha1A expression does not mirror the localized pattern of cerebellar degeneration observed in tg(la) mice, providing evidence for regional differences in biological function of alpha1A channels [6].
  • Axon branches of the locus coeruleus, a noradrenergic brain-stem nucleus, hyperinnervate specific target regions of the tg brain [7].
  • Mice with the mutant gene tottering (tg, chromosome 8, autosomal recessive) show, in adolescence, abnormal bursts of bilaterally synchronous spike waves as revealed in electrocorticograms recorded over long periods [8].
  • We studied cardiac pressure overload in mice with double KO of the 2 main alpha1-AR subtypes in the heart, alpha 1A (Adra1a) and alpha 1B (Adra1b) [9].
 

Biological context of Cacna1a

  • The Cacna2d2(tm1NCIF) null phenotype has much in common with that of Cacna1a mutants, such as cerebellar neuro-degeneration associated with ataxia, seizures, and premature death [10].
  • Alternative splicings of the Cacna1a transcript have been postulated to contribute to the respective properties, however, the splice variants responsible for P-type Ca(2+) channels have not been identified [11].
  • In this study, we mapped gry on rat chromosome 19 and found a nonconservative missense (M251K) mutation in the alpha(1A) subunit of the P/Q-type voltage-gated Ca(2+) channel gene (Cacna1a) within the gry-critical region [2].
  • Electrophysiological and immunostaining data support a predominant role for Cav2.1 subunits in mediating action potential-evoked inhibitory GABA release onto mouse Purkinje cells [12].
  • Opioidergic and dopaminergic gene expression in the caudate-putamen and accumbens of the mutant mouse, tottering (tg/tg) [13].
 

Anatomical context of Cacna1a

  • Transmitter release at the wild-type neuromuscular junction (NMJ) is almost exclusively mediated by Cav2.1 channels, and we used this model synapse to study synaptic consequences of the Tg mutation [14].
  • Cav2.1 staining was colocalized with staining for antibodies against glutamic acid decarboxylase and corresponded well with the pericellular network formed by GABAergic basket cell interneurons [12].
  • Injection of cDNAs encoding the alpha1A, alpha1B, alpha1C, and alpha1E subunits into oocytes showed that tBHQ blocked ICas at the level of the pore-forming protein [15].
  • The calcium channel alpha1A subunit gene encodes the pore-forming protein of P/Q-type voltage-dependent calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons with moderate expression in hippocampus and inferior colliculus [16].
  • Dynamic association of the Ca2+ channel alpha1A subunit and SNAP-25 in round or neurite-emitting chromaffin cells [17].
 

Associations of Cacna1a with chemical compounds

  • We found a Ca(2+)-, Mg(2+)- and K(+)-dependent increase of spontaneous ACh release at both homo- and heterozygote tg NMJs [18].
  • To assess whether alpha(1A) mutations influence neurotransmitter release, we studied P-type Ca(2+) channel-mediated acetylcholine (ACh) release at tg neuromuscular junctions (NMJs) with micro-electrode measurements of synaptic potentials [18].
  • Comparison of the effects of increased potassium and of adenosine on hippocampal neurons from normal and genetically epileptic tg/tg mice [19].
  • These results indicate that the expression of the alpha1A subunit was decreased in terminals from tottering mice, and that a decreased contribution of P- and Q-type Ca2+-channels to the release of glutamate and cholecystokinin was functionally compensated by an increased contribution of N-type Ca2+-channels [20].
  • Chloride loading prolonged PDS duration in both genotypes, but the increase was greater in +/+ than in tg/tg neurons, indicating that a smaller GABAA inhibitory postsynaptic potential (IPSP) component was reversed in the mutant.(ABSTRACT TRUNCATED AT 400 WORDS)[21]
 

Physical interactions of Cacna1a

 

Co-localisations of Cacna1a

  • However, during the first stages of the cell transdifferentiation process, SNAP-25 migrates alone out to the developing growth cone and what will become the nerve endings and varicosities of the mature neurites; alpha1A follows and colocalizes to SNAP-25 in the now mature processes [17].
 

Regulatory relationships of Cacna1a

  • We conclude that several properties of alpha1A and alpha1B proteins are not uniquely regulated by beta4 in vivo and may be rescued by beta1-3 subunit reshuffling [22].
  • P/Q-type Ca2+ channel alpha1A mRNA was expressed at a higher level in olfactory bulb of homozygous alpha1B-deficient mice than wild-type or heterozygous mice [23].
 

Other interactions of Cacna1a

  • Probably, there is a small reduction in functional presynaptic Cav2.1 channels at Tg NMJs, which is compensated for by Cav2.3 channels [14].
  • Based upon these observations, we conclude that Ctxn is not involved in the genetic defects found in nr, tg or mnd mice [24].
  • 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 [25].
  • Selective antibodies directed against the Cav2.1 subunit revealed staining in regions closely opposed to Purkinje cell somata [12].
  • The tg mutation was localized to the 1.1 cM region of chromosome 8 distal to simple sequence repeat (SSR) D8Mit103 and proximal to SSRs D8Mit79, D8Mit105, and D8Mit283 [26].
 

Analytical, diagnostic and therapeutic context of Cacna1a

  • Complementation tests with the leaner mutant allele (Cacna1a(la)) produced mutant animals, thus identifying rocker as a new allele of Cacna1a (Cacna1a(rkr)) [27].
  • Here, we have used whole-cell recordings to determine whether the leaner mutation alters calcium channel currents in cerebellar Purkinje cells, both because these cells are profoundly affected in leaner mice and because they normally express high levels of alpha1A [4].
  • To identify the members of the voltage-dependent Ca2+ channel family possibly present in sperm, we have looked for the expression of the alpha 1A, alpha 1B, alpha 1C, alpha 1D and alpha 1E genes in mouse testis and in purified spermatogenic cell populations with RT-PCR [28].
  • Western blot analysis demonstrated significant alpha1C protein subunit expression, with less alpha1D subunit apparent, while alpha1A, alpha1B and alpha1E subunit expression was undetectable [29].
  • The distribution of alpha1A and SNAP-25 was studied in round or transdifferentiated chromaffin cells using confocal microscopy and specific antibodies: the two proteins are colocalized at the cell body membrane in both natural cell types [17].

References

  1. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. van den Maagdenberg, A.M., Pietrobon, D., Pizzorusso, T., Kaja, S., Broos, L.A., Cesetti, T., van de Ven, R.C., Tottene, A., van der Kaa, J., Plomp, J.J., Frants, R.R., Ferrari, M.D. Neuron (2004) [Pubmed]
  2. The ataxic groggy rat has a missense mutation in the P/Q-type voltage-gated Ca(2+) channel alpha(1A) subunit gene and exhibits absence seizures. Tokuda, S., Kuramoto, T., Tanaka, K., Kaneko, S., Takeuchi, I.K., Sasa, M., Serikawa, T. Brain Res. (2007) [Pubmed]
  3. Eye movements of the murine P/Q calcium channel mutant tottering, and the impact of aging. Stahl, J.S., James, R.A., Oommen, B.S., Hoebeek, F.E., De Zeeuw, C.I. J. Neurophysiol. (2006) [Pubmed]
  4. Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner. Lorenzon, N.M., Lutz, C.M., Frankel, W.N., Beam, K.G. J. Neurosci. (1998) [Pubmed]
  5. The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis. Koshy, B.T., Zoghbi, H.Y. Brain Pathol. (1997) [Pubmed]
  6. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Fletcher, C.F., Lutz, C.M., O'Sullivan, T.N., Shaughnessy, J.D., Hawkes, R., Frankel, W.N., Copeland, N.G., Jenkins, N.A. Cell (1996) [Pubmed]
  7. A single gene error of noradrenergic axon growth synchronizes central neurones. Noebels, J.L. Nature (1984) [Pubmed]
  8. Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Noebels, J.L., Sidman, R.L. Science (1979) [Pubmed]
  9. Alpha1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload. O'Connell, T.D., Swigart, P.M., Rodrigo, M.C., Ishizaka, S., Joho, S., Turnbull, L., Tecott, L.H., Baker, A.J., Foster, E., Grossman, W., Simpson, P.C. J. Clin. Invest. (2006) [Pubmed]
  10. Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene. Ivanov, S.V., Ward, J.M., Tessarollo, L., McAreavey, D., Sachdev, V., Fananapazir, L., Banks, M.K., Morris, N., Djurickovic, D., Devor-Henneman, D.E., Wei, M.H., Alvord, G.W., Gao, B., Richardson, J.A., Minna, J.D., Rogawski, M.A., Lerman, M.I. Am. J. Pathol. (2004) [Pubmed]
  11. Novel Cav2.1 splice variants isolated from Purkinje cells do not generate P-type Ca2+ current. Tsunemi, T., Saegusa, H., Ishikawa, K., Nagayama, S., Murakoshi, T., Mizusawa, H., Tanabe, T. J. Biol. Chem. (2002) [Pubmed]
  12. The Cav2.1/alpha1A (P/Q-type) voltage-dependent calcium channel mediates inhibitory neurotransmission onto mouse cerebellar Purkinje cells. Stephens, G.J., Morris, N.P., Fyffe, R.E., Robertson, B. Eur. J. Neurosci. (2001) [Pubmed]
  13. Opioidergic and dopaminergic gene expression in the caudate-putamen and accumbens of the mutant mouse, tottering (tg/tg). De Bartolomeis, A., Koprivica, V., Pickar, D., Crawley, J.N., Abbott, L.C. Brain Res. Mol. Brain Res. (1997) [Pubmed]
  14. Compensatory contribution of Cav2.3 channels to acetylcholine release at the neuromuscular junction of tottering mice. Kaja, S., Van de Ven, R.C., Ferrari, M.D., Frants, R.R., Van den Maagdenberg, A.M., Plomp, J.J. J. Neurophysiol. (2006) [Pubmed]
  15. Sarco-endoplasmic ATPase blocker 2,5-Di(tert-butyl)-1, 4-benzohydroquinone inhibits N-, P-, and Q- but not T-, L-, or R-type calcium currents in central and peripheral neurons. Scamps, F., Vigues, S., Restituito, S., Campo, B., Roig, A., Charnet, P., Valmier, J. Mol. Pharmacol. (2000) [Pubmed]
  16. L-type calcium channels contribute to the tottering mouse dystonic episodes. Campbell, D.B., Hess, E.J. Mol. Pharmacol. (1999) [Pubmed]
  17. Dynamic association of the Ca2+ channel alpha1A subunit and SNAP-25 in round or neurite-emitting chromaffin cells. Andrés-Mateos, E., Renart, J., Cruces, J., Solís-Garrido, L.M., Serantes, R., de Lucas-Cerrillo, A.M., Aldea, M., García, A.G., Montiel, C. Eur. J. Neurosci. (2005) [Pubmed]
  18. Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering alpha(1A) Ca(2+) channel mutation. Plomp, J.J., Vergouwe, M.N., Van den Maagdenberg, A.M., Ferrari, M.D., Frants, R.R., Molenaar, P.C. Brain (2000) [Pubmed]
  19. Comparison of the effects of increased potassium and of adenosine on hippocampal neurons from normal and genetically epileptic tg/tg mice. Psarropoulou, C., Kostopoulos, G. Epilepsia (1993) [Pubmed]
  20. Neurotransmitter release from tottering mice nerve terminals with reduced expression of mutated P- and Q-type Ca2+-channels. Leenders, A.G., van den Maagdenberg, A.M., Lopes da Silva, F.H., Sheng, Z.H., Molenaar, P.C., Ghijsen, W.E. Eur. J. Neurosci. (2002) [Pubmed]
  21. Analysis of voltage-gated and synaptic conductances contributing to network excitability defects in the mutant mouse tottering. Helekar, S.A., Noebels, J.L. J. Neurophysiol. (1994) [Pubmed]
  22. 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]
  23. Expression analysis of P/Q-type Ca2+ channel alpha 1A subunit mRNA in olfactory mitral cell in N-type Ca2+ channel alpha 1B subunit gene-deficient mice. Takahashi, E., Ino, M., Miyamoto, N., Nagasu, T. Neurosci. Lett. (2004) [Pubmed]
  24. Probable exclusion of the cortexin-encoding gene as a candidate for mouse neurological mutants: nervous, tottering and motor neuron degeneration. Horvath, D.H., Watson, J.B., Travis, G.H. Gene (1996) [Pubmed]
  25. 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]
  26. Chromosomal localization of the neurological mouse mutations tottering (tg), Purkinje cell degeneration (pcd), and nervous (nr). Campbell, D.B., Hess, E.J. Brain Res. Mol. Brain Res. (1996) [Pubmed]
  27. Rocker is a new variant of the voltage-dependent calcium channel gene Cacna1a. Zwingman, T.A., Neumann, P.E., Noebels, J.L., Herrup, K. J. Neurosci. (2001) [Pubmed]
  28. T-type Ca2+ channels and alpha1E expression in spermatogenic cells, and their possible relevance to the sperm acrosome reaction. Liévano, A., Santi, C.M., Serrano, C.J., Treviño, C.L., Bellvé, A.R., Hernández-Cruz, A., Darszon, A. FEBS Lett. (1996) [Pubmed]
  29. Functional expression of L- and T-type Ca2+ channels in murine HL-1 cells. Xia, M., Salata, J.J., Figueroa, D.J., Lawlor, A.M., Liang, H.A., Liu, Y., Connolly, T.M. J. Mol. Cell. Cardiol. (2004) [Pubmed]
 
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