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N terminus is key to the dominant negative suppression of CaV2 calcium channels: implications for episodic ataxia type 2

Page, K. M.; Heblich, F.; Margas, W.; Pratt, W. S.; Nieto-Rostro, M.; Chaggar, K.; Sandhu, K.; ... Dolphin, A. C.; + view all (2010) N terminus is key to the dominant negative suppression of CaV2 calcium channels: implications for episodic ataxia type 2. Journal of Biological Chemistry , 285 (2) pp. 835-844. 10.1074/jbc.M109.065045. Green open access

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Abstract

Expression of the calcium channels CaV2.1 and CaV2.2 is markedly suppressed by co-expression with truncated constructs containing Domain I. This is the basis for the phenomenon of dominant negative suppression observed for many of the episodic ataxia type 2 mutations in CaV2.1 that predict truncated channels. The process of dominant negative suppression has been shown previously to stem from interaction between the full-length and truncated channels and to result in downstream consequences of the unfolded protein response and endoplasmic reticulum-associated protein degradation. We have now identified the specific domain that triggers this effect. For both CaV2.1 and CaV2.2, the minimum construct producing suppression was the cytoplasmic N terminus. Suppression was enhanced by tethering the N terminus to the membrane with a CAAX motif. The 11-amino acid motif (including Arg52 and Arg54) within the N terminus, which we have previously shown to be required for G protein modulation, is also essential for dominant negative suppression. Suppression is prevented by addition of an N-terminal tag (XFP) to the full-length and truncated constructs. We further show that suppression of CaV2.2 currents by the N terminus-CAAX construct is accompanied by a reduction in CaV2.2 protein level, and this is also prevented by mutation of Arg52 and Arg54 to Ala in the truncated construct. Taken together, our evidence indicates that both the extreme N terminus and the Arg52, Arg54 motif are involved in the processes underlying dominant negative suppression.

Type: Article
Title: N terminus is key to the dominant negative suppression of CaV2 calcium channels: implications for episodic ataxia type 2
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.M109.065045
Publisher version: http://dx.doi.org/10.1074/jbc.M109.065045
Language: English
Additional information: This research was originally published in Journal of Biological Chemistry. Page, K. M. and Heblich, F. and Margas, W. and Pratt, W. S. and Nieto-Rostro, M. and Chaggar, K. and Sandhu, K. and Davies, A. and Dolphin, A. C. N terminus is key to the dominant negative suppression of CaV2 calcium channels: implications for episodic ataxia type 2. Journal of Biological Chemistry, 2010. 285 (2). pp. 835-844. © the American Society for Biochemistry and Molecular Biology.
Keywords: Biophysics, calcium/channels, channels/calcium, diseases, diseases/neurological, neurochemistry, neurobiology/neuroscience
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/20043
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