WWW.JNEUROSCI.ORG
-
The Journal of Neuroscience
QUICK SEARCH:   [advanced]


     
-


HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP
The Journal of Neuroscience, August 23, 2006, 26(34):8748-8757; doi:10.1523/JNEUROSCI.2764-06.2006

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit an eLetter
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (26)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Davies, A.
Right arrow Articles by Dolphin, A. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Davies, A.
Right arrow Articles by Dolphin, A. C.

 Previous Article  |  Next Article 

Cellular/Molecular
The Calcium Channel {alpha}2{delta}-2 Subunit Partitions with CaV2.1 into Lipid Rafts in Cerebellum: Implications for Localization and Function

Anthony Davies,1 * Leon Douglas,1 * Jan Hendrich,1 * Jack Wratten,1 Alexandra Tran Van Minh,1 Isabelle Foucault,1 Dietlind Koch,1 Wendy S. Pratt,1 Helen R. Saibil,2 and Annette C. Dolphin1

1Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, and 2School of Crystallography, Birkbeck, University of London, London WC1E 7HX, United Kingdom

Correspondence should be addressed to Annette C. Dolphin, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: a.dolphin{at}ucl.ac.uk

The accessory {alpha}2{delta} subunits of voltage-gated calcium channels are highly glycosylated transmembrane proteins that interact with calcium channel {alpha}1 subunits to enhance calcium currents. We compared the membrane localization and processing of native cerebellar {alpha}2{delta}-2 subunits with {alpha}2{delta}-2 stably expressed in tsA-201 cells. We identified that {alpha}2{delta}-2 is completely concentrated in cholesterol-rich microdomains (lipid rafts) in cerebellum, in which it substantially colocalizes with the calcium channel {alpha}1 subunit CaV2.1, although CaV2.1 is also present in the Triton X-100-soluble fraction. In tsA-201 cells, unlike cerebellum, {alpha}2{delta}-2 is not completely proteolytically processed into {alpha}2-2 and {delta}-2. However, this processing is more complete in the lipid raft fraction of tsA-201 cells, in which {alpha}2{delta}-2 also colocalizes with CaV2.1. Cholesterol depletion of intact cells disrupted their lipid rafts and enhanced CaV2.1/{alpha}2{delta}-2/beta4 currents. Furthermore, {alpha}2{delta}-2 coimmunoprecipitates with lipid raft-associated proteins of the stomatin family. The apparent affinity of {alpha}2{delta}-2 for its ligand gabapentin is increased markedly in the cholesterol-rich microdomain fractions, in both cerebellum and the stable {alpha}2{delta}-2 cell line. In contrast, {alpha}2{delta}-2 containing a point mutation (R282A) has a much lower affinity for gabapentin, and this is not enhanced in the lipid raft fraction. This R282A mutant {alpha}2{delta}-2 shows reduced functionality in terms of enhancement of CaV2.1/beta4 calcium currents, suggesting that the integrity of the gabapentin binding site may be important for normal functioning of {alpha}2{delta}-2. Together, these results indicate that both {alpha}2{delta}-2 and CaV2.1 are normally associated with cholesterol-rich microdomains, and this influences their functionality.

Key words: calcium; channel; {alpha}2{delta}; gabapentin; lipid raft; cerebellum; cholesterol

Received April 13, 2006; revised July 17, 2006; accepted July 17, 2006.

Correspondence should be addressed to Annette C. Dolphin, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: a.dolphin{at}ucl.ac.uk




This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
S. Oldfield, J. Hancock, A. Mason, S. A. Hobson, D. Wynick, E. Kelly, A. D. Randall, and N. V. Marrion
Receptor-Mediated Suppression of Potassium Currents Requires Colocalization within Lipid Rafts
Mol. Pharmacol., December 1, 2009; 76(6): 1279 - 1289.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Watanabe, H. Wake, A. J. Moorhouse, and J. Nabekura
Clustering of Neuronal K+-Cl- Cotransporters in Lipid Rafts by Tyrosine Phosphorylation
J. Biol. Chem., October 9, 2009; 284(41): 27980 - 27988.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
J. A. Wang, W. Lin, T. Morris, U. Banderali, P. F. Juranka, and C. E. Morris
Membrane trauma and Na+ leak from Nav1.6 channels
Am J Physiol Cell Physiol, October 1, 2009; 297(4): C823 - C834.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
J. J. Plomp and H. J. Willison
Pathophysiological actions of neuropathy-related anti-ganglioside antibodies at the neuromuscular junction
J. Physiol., August 15, 2009; 587(16): 3979 - 3999.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. S. Bauer, M. Nieto-Rostro, W. Rahman, A. Tran-Van-Minh, L. Ferron, L. Douglas, I. Kadurin, Y. Sri Ranjan, L. Fernandez-Alacid, N. S. Millar, et al.
The Increased Trafficking of the Calcium Channel Subunit {alpha}2{delta}-1 to Presynaptic Terminals in Neuropathic Pain Is Inhibited by the {alpha}2{delta} Ligand Pregabalin
J. Neurosci., April 1, 2009; 29(13): 4076 - 4088.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Hendrich, A. T. Van Minh, F. Heblich, M. Nieto-Rostro, K. Watschinger, J. Striessnig, J. Wratten, A. Davies, and A. C. Dolphin
Pharmacological disruption of calcium channel trafficking by the {alpha}2{delta} ligand gabapentin
PNAS, March 4, 2008; 105(9): 3628 - 3633.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
D. P. McEwen, Q. Li, S. Jackson, P. M. Jenkins, and J. R. Martens
Caveolin Regulates Kv1.5 Trafficking to Cholesterol-Rich Membrane Microdomains
Mol. Pharmacol., March 1, 2008; 73(3): 678 - 685.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
H.-J. Kim, X. Fan, C. Gabbi, K. Yakimchuk, P. Parini, M. Warner, and J.-A. Gustafsson
Liver X receptor {beta} (LXR{beta}): A link between {beta}-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia
PNAS, February 12, 2008; 105(6): 2094 - 2099.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
R. Donato, K. M. Page, D. Koch, M. Nieto-Rostro, I. Foucault, A. Davies, T. Wilkinson, M. Rees, F. A. Edwards, and A. C. Dolphin
The ducky2J Mutation in Cacna2d2 Results in Reduced Spontaneous Purkinje Cell Activity and Altered Gene Expression
J. Neurosci., November 29, 2006; 26(48): 12576 - 12586.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. J. Field, P. J. Cox, E. Stott, H. Melrose, J. Offord, T.-Z. Su, S. Bramwell, L. Corradini, S. England, J. Winks, et al.
Identification of the {alpha}2-{delta}-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin
PNAS, November 14, 2006; 103(46): 17537 - 17542.
[Abstract] [Full Text] [PDF]


-
-

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help
-
Copyright 2009 by Society for Neuroscience ONLINE ISSN: 1529-2401
-