Journal article
N-terminal isoforms of the large-conductance Ca²⁺-activated K⁺ channel are differentially modulated by the auxiliary β1-subunit
The Journal of biological chemistry, Vol.289(14), pp.10095-10103
04/04/2014
DOI: 10.1074/jbc.M113.521526
PMCID: PMC3974980
PMID: 24569989
Abstract
The large-conductance Ca(2+)-activated K(+) (BK(Ca)) channel is essential for maintaining the membrane in a hyperpolarized state, thereby regulating neuronal excitability, smooth muscle contraction, and secretion. The BK(Ca) α-subunit has three predicted initiation codons that generate proteins with N-terminal ends starting with the amino acid sequences MANG, MSSN, or MDAL. Because the N-terminal region and first transmembrane domain of the α-subunit are required for modulation by auxiliary β1-subunits, we examined whether β1 differentially modulates the N-terminal BK(Ca) α-subunit isoforms. In the absence of β1, all isoforms had similar single-channel conductances and voltage-dependent activation. However, whereas β1 did not modulate the voltage-activation curve of MSSN, β1 induced a significant leftward shift of the voltage activation curves of both the MDAL and MANG isoforms. These shifts, of which the MDAL was larger, occurred at both 10 μM and 100 μM Ca(2+). The β1-subunit increased the open dwell times of all three isoforms and decreased the closed dwell times of MANG and MDAL but increased the closed dwell times of MSSN. The distinct modulation of voltage activation by the β1-subunit may be due to the differential effect of β1 on burst duration and interburst intervals observed among these isoforms. Additionally, we observed that the related β2-subunit induced comparable leftward shifts in the voltage-activation curves of all three isoforms, indicating that the differential modulation of these isoforms was specific to β1. These findings suggest that the relative expression of the N-terminal isoforms can fine-tune BK(Ca) channel activity in cells, highlighting a novel mechanism of BK(Ca) channel regulation.
Details
- Title: Subtitle
- N-terminal isoforms of the large-conductance Ca²⁺-activated K⁺ channel are differentially modulated by the auxiliary β1-subunit
- Creators
- Ramón A Lorca - Washington University in St. Louis School of MedicineSusan J Stamnes - University of IowaMeghan K Pillai - Washington University in St. Louis School of MedicineJordy J Hsiao - University of IowaMichael E Wright - University of Iowa, Molecular Physiology and BiophysicsSarah K England - Washington University in St. Louis School of Medicine
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.289(14), pp.10095-10103
- DOI
- 10.1074/jbc.M113.521526
- PMID
- 24569989
- PMCID
- PMC3974980
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- United States
- Grant note
- M01 RR000059 / NCRR NIH HHS M01-RR-00059 / NCRR NIH HHS R01 HD037831 / NICHD NIH HHS
- Language
- English
- Date published
- 04/04/2014
- Academic Unit
- Molecular Physiology and Biophysics
- Record Identifier
- 9983759098302771
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