Journal article
Functional impact of a congenital stationary night blindness type 2 mutation depends on subunit composition of Cav1.4 Ca2+ channels
The Journal of biological chemistry, Vol.295(50), pp.17215-17226
12/11/2020
DOI: 10.1074/jbc.RA120.014138
PMCID: PMC7863891
PMID: 33037074
Abstract
Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary β (β1-4) and α2δ (α2δ−1−4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, β2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β2X13 and α2δ-4 but not in those with β2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.
Details
- Title: Subtitle
- Functional impact of a congenital stationary night blindness type 2 mutation depends on subunit composition of Cav1.4 Ca2+ channels
- Creators
- Brittany Williams - Departments of Molecular Physiology and Biophysics, Otolaryngology Head-Neck Surgery, and Neurology, Iowa Neuroscience Institute, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa USAJosue A Lopez - Departments of Molecular Physiology and Biophysics, Otolaryngology Head-Neck Surgery, and Neurology, Iowa Neuroscience Institute, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa USAJ. Wesley Maddox - Departments of Molecular Physiology and Biophysics, Otolaryngology Head-Neck Surgery, and Neurology, Iowa Neuroscience Institute, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa USAAmy Lee - Departments of Molecular Physiology and Biophysics, Otolaryngology Head-Neck Surgery, and Neurology, Iowa Neuroscience Institute, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa USA
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.295(50), pp.17215-17226
- DOI
- 10.1074/jbc.RA120.014138
- PMID
- 33037074
- PMCID
- PMC7863891
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- name: NIH, award: EY026817; name: NIH, award: EY026477; name: NIH, award: EY029953; name: NIH, award: NS007421; name: NIH, award: GM058939; name: NIH, award: NS045549
- Language
- English
- Date published
- 12/11/2020
- Academic Unit
- Molecular Physiology and Biophysics
- Record Identifier
- 9984071793702771
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