Journal article
Inhibition of Recombinant N-Type CaV Channels by the γ2 Subunit Involves Unfolded Protein Response (UPR)-Dependent and UPR-Independent Mechanisms
The Journal of neuroscience, Vol.27(12), pp.3317-3327
03/21/2007
DOI: 10.1523/JNEUROSCI.4566-06.2007
PMID: 17376992
Abstract
Auxiliary γ subunits are an important component of high-voltage-activated calcium (Ca
V
) channels, but their precise regulatory role remains to be determined. In the current report, we have used complementary approaches including molecular biology and electrophysiology to investigate the influence of the γ subunits on neuronal Ca
V
channel activity and expression. We found that coexpression of γ
2
or γ
3
subunits drastically inhibited macroscopic currents through recombinant N-type channels (Ca
V
2.2/β
3
/α
2
δ) in HEK-293 cells. Using inhibitors of internalization, we found that removal of functional channels from the plasma membrane is an improbable mechanism of current regulation by γ. Instead, changes in current amplitude could be attributed to two distinct mechanisms. First, γ subunit expression altered the voltage dependence of channel activity. Second, γ subunit expression reduced N-type channel synthesis via activation of the endoplasmic reticulum unfolded protein response. Together, our findings (1) corroborate that neuronal γ subunits significantly downregulate Ca
V
2.2 channel activity, (2) uncover a role for the γ
2
subunit in Ca
V
2.2 channel expression through early components of the biosynthetic pathway, and (3) suggest that, under certain conditions, channel protein misfolding could be induced by interactions with the γ subunits, supporting the notion that Ca
V
channels constitute a class of difficult-to-fold proteins.
Details
- Title: Subtitle
- Inhibition of Recombinant N-Type CaV Channels by the γ2 Subunit Involves Unfolded Protein Response (UPR)-Dependent and UPR-Independent Mechanisms
- Creators
- Alejandro Sandoval - Departments of Physiology, Biophysics, and Neuroscience, andArturo Andrade - Departments of Physiology, Biophysics, and Neuroscience, andAaron M Beedle - Howard Hughes Medical Institute and Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242-1101Kevin P Campbell - Howard Hughes Medical Institute and Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242-1101Ricardo Felix - Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, Mexico City, 07300, Mexico
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.27(12), pp.3317-3327
- DOI
- 10.1523/JNEUROSCI.4566-06.2007
- PMID
- 17376992
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Publisher
- Society for Neuroscience
- Language
- English
- Date published
- 03/21/2007
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984020782902771
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