N-terminal isoforms of the large-conductance Ca²?-activated K? channel are differentially modulated by the auxiliary ?1-subunit.
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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) ?-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 ?-subunit are required for modulation by auxiliary ?1-subunits, we examined whether ?1 differentially modulates the N-terminal BK(Ca) ?-subunit isoforms. In the absence of ?1, all isoforms had similar single-channel conductances and voltage-dependent activation. However, whereas ?1 did not modulate the voltage-activation curve of MSSN, ?1 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 ?M and 100 ?M Ca(2+). The ?1-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 ?1-subunit may be due to the differential effect of ?1 on burst duration and interburst intervals observed among these isoforms. Additionally, we observed that the related ?2-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 ?1. 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.
SUBMITTER: Lorca RA
PROVIDER: S-EPMC3974980 | biostudies-literature | 2014 Apr
REPOSITORIES: biostudies-literature
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