S-Acylation controls functional coupling of BK channel pore-forming α-subunits and β1-subunits

被引:11
作者
Duncan, Peter J. [1 ]
Bi, Danlei [1 ,2 ]
McClafferty, Heather [1 ]
Chen, Lie [1 ,3 ]
Tian, Lijun [1 ]
Shipston, Michael J. [1 ]
机构
[1] Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh Med Sch Biomed Sci, Edinburgh EH8 9XD, Midlothian, Scotland
[2] Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China
[3] Univ Brunei Darussalam, PAPRSB Inst Hlth Sci, BE-1410 Gadong, Brunei
基金
英国惠康基金;
关键词
protein acylation; acyltransferase; protein palmitoylation; potassium channel; ion channel; post-translational modification (PTM); Kcnma1; Kcnmb1; lipid modification; protein trafficking; CONTROL SURFACE EXPRESSION; CA2+-ACTIVATED K+ CHANNEL; POTASSIUM CHANNEL; BETA-1; SUBUNIT; BLOOD-PRESSURE; SMOOTH-MUSCLE; VOLTAGE; PALMITOYLATION; MODULATION; PHYSIOLOGY;
D O I
10.1074/jbc.RA119.009065
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The properties and physiological function of pore-forming alpha-subunits of large conductance calcium- and voltage-activated potassium (BK) channels are potently modified by their functional coupling with regulatory subunits in many tissues. However, mechanisms that might control functional coupling are very poorly understood. Here we show that S-acylation, a dynamic post-translational lipid modification of proteins, of the intracellular S0-S1 loop of the BK channel pore-forming alpha-subunit controls functional coupling to regulatory beta 1-subunits. In HEK293 cells, alpha-subunits that cannot be S-acylated show attenuated cell surface expression, but expression was restored by co-expression with the beta 1-subunit. However, we also found that nonacylation of the S0-S1 loop reduces functional coupling between alpha- and beta 1-subunits by attenuating the beta 1-subunit-induced left shift in the voltage for half-maximal activation. In mouse vascular smooth muscle cells expressing both alpha- and beta 1-subunits, BK channel alpha-subunits were endogenously S-acylated. We further noted that S-acylation is significantly reduced in mice with a genetic deletion of the palmitoyl acyltransferase (Zdhhc23) that controls S-acylation of the S0-S1 loop. Genetic deletion of Zdhhc23 or broad-spectrum pharmacological inhibition of S-acylation attenuated endogenous BK channel currents independently of changes in cell surface expression of the alpha-subunit. We conclude that functional effects of S-acylation on BK channels depend on the presence of beta 1-subunits. In the absence of beta 1-subunits, S-acylation promotes cell surface expression, whereas in its presence, S-acylation controls functional coupling. S-Acylation thus provides a mechanism that dynamically regulates the functional coupling with beta 1-subunits, enabling an additional level of conditional, cell-specific control of ion-channel physiology.
引用
收藏
页码:12066 / 12076
页数:11
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