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Title: MitoBK Ca channel is functionally associated with its regulatory β1 subunit in cardiac mitochondria
Key points

Association of plasma membrane BKCachannels with BK‐β subunits shapes their biophysical properties and physiological roles; however, functional modulation of the mitochondrial BKCachannel (mitoBKCa) by BK‐β subunits is not established.

MitoBKCa‐α and the regulatory BK‐β1 subunit associate in mouse cardiac mitochondria.

A large fraction of mitoBKCadisplay properties similar to that of plasma membrane BKCawhen associated with BK‐β1 (left‐shifted voltage dependence of activation,V1/2 = −55 mV, 12 µmmatrix Ca2+).

In BK‐β1 knockout mice, cardiac mitoBKCadisplayed a lowPoand a depolarizedV1/2of activation (+47 mV at 12 µmmatrix Ca2+)

Co‐expression of BKCawith the BK‐β1 subunit in HeLa cells doubled the density of BKCain mitochondria.

The present study supports the view that the cardiac mitoBKCachannel is functionally modulated by the BK‐β1 subunit; proper targeting and activation of mitoBKCashapes mitochondrial Ca2+handling.


Association of the plasma membrane BKCachannel with auxiliary BK‐β1–4 subunits profoundly affects the regulatory mechanisms and physiological processes in which this channel participates. However, functional association of mitochondrial BK (mitoBKCa) with regulatory subunits is unknown. We report that mitoBKCafunctionally associates with its regulatory subunit BK‐β1 in adult rodent cardiomyocytes. Cardiac mitoBKCais a calcium‐ and voltage‐activated channel that is sensitive to paxilline with a large conductance for K+of 300 pS. Additionally, mitoBKCadisplays a high open probability (Po) and voltage half‐activation (V1/2 = −55 mV,n = 7) resembling that of plasma membrane BKCawhen associated with its regulatory BK‐β1 subunit. Immunochemistry assays demonstrated an interaction between mitochondrial BKCa‐α and its BK‐β1 subunit. Mitochondria from the BK‐β1 knockout (KO) mice showed sparse mitoBKCacurrents (five patches with mitoBKCaactivity out of 28 total patches fromn = 5 different hearts), displaying a depolarizedV1/2of activation (+47 mV in 12 µmmatrix Ca2+). The reduced activity of mitoBKCawas accompanied by a high expression of BKCatranscript in the BK‐β1 KO, suggesting a lower abundance of mitoBKCachannels in this genotype. Accordingly, BK‐β1subunit increased the localization of BKDEC (i.e. the splice variant of BKCathat specifically targets mitochondria) into mitochondria by two‐fold. Importantly, both paxilline‐treated and BK‐β1 KO mitochondria displayed a more rapid Ca2+overload, featuring an early opening of the mitochondrial transition pore. We provide strong evidence that mitoBKCaassociates with its regulatory BK‐β1 subunit in cardiac mitochondria, ensuring proper targeting and activation of the mitoBKCachannel that helps to maintain mitochondrial Ca2+homeostasis.

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Author(s) / Creator(s):
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Publisher / Repository:
Date Published:
Journal Name:
The Journal of Physiology
Page Range / eLocation ID:
p. 3817-3832
Medium: X
Sponsoring Org:
National Science Foundation
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