Regulation of BK channel expression by Paraoxonase 3.

Paraoxonase 3 (PON3) is a molecular chaperone that is primarily expressed in the aldosterone-sensitive distal nephron (ASDN) where the fine tuning of Na+ and K+ homeostasis occurs. The flow-induced K+ secretion in the distal nephron is mediated by large conductance Ca2+ -activated K+ (BK) channels in intercalated cells (ICs). As PON3 co-localizes with BK in the ICs and Pon3 KO mice have altered blood [K+ ] at baseline, we hypothesize that PON3 has a role in regulating BK expression and functional activity. To determine whether the functional expression of BK channels is regulated by PON3, the pore-forming α subunits of mouse BK (αBK) was expressed in HEK293 cells with or without mouse PON3. We performed co-immunoprecipitation (co-IP) to examine whether PON3 interacts with αBK. We also examined the effects of PON3 on αBK expression and BK channel activity using biochemical and electrophysiological approaches. When expressed in HEK293 cells, PON3 was pulled down by the αBK-IP while αBK was detected in the PON3-pulldown, only in cells expressing both proteins. Our data suggest that there are direct or indirect interactions between PON3 and αBK, the pore-forming subunit of BK channels. We performed whole cell patch clamp to measure BK channel activity in HEK293 cells. we found that IBTX-sensitive whole cell K+ currents were reduced approximately 50% by PON3. Consistently, both whole cell and surface abundance of αBK was significantly lower in cells co-expressing PON3. Together, our data suggest that PON3 negatively regulates the expression and activity of BK channels. In conclusion, we identified the BK channel as a novel target of the chaperone PON3. Future studies will determine mechanisms by which PON3 regulates BK channel functional expression as well as physiological consequences of this regulatory interaction in mouse kidney. © FASEB.

Citation

Shujie Shi, Nicolas Montalbetti, Thomas Kleyman. Regulation of BK channel expression by Paraoxonase 3. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 May;36 Suppl 1

PMID: 35555214

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