BK Channel Modulation by Leucine-Rich Repeat Containing Proteins

Section of Neurobiology, Center for Learning and Memory, University of Texas, Austin, TX 78712, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2012; 109(20):7917-22. DOI: 10.1073/pnas.1205435109
Source: PubMed

ABSTRACT Molecular diversity of ion channel structure and function underlies variability in electrical signaling in nerve, muscle, and nonexcitable cells. Regulation by variable auxiliary subunits is a major mechanism to generate tissue- or cell-specific diversity of ion channel function. Mammalian large-conductance, voltage- and calcium-activated potassium channels (BK, K(Ca)1.1) are ubiquitously expressed with diverse functions in different tissues or cell types, consisting of the pore-forming, voltage- and Ca(2+)-sensing α-subunits (BKα), either alone or together with the tissue-specific auxiliary β-subunits (β1-β4). We recently identified a leucine-rich repeat (LRR)-containing membrane protein, LRRC26, as a BK channel auxiliary subunit, which causes an unprecedented large negative shift (∼140 mV) in voltage dependence of channel activation. Here we report a group of LRRC26 paralogous proteins, LRRC52, LRRC55, and LRRC38 that potentially function as LRRC26-type auxiliary subunits of BK channels. LRRC52, LRRC55, and LRRC38 produce a marked shift in the BK channel's voltage dependence of activation in the hyperpolarizing direction by ∼100 mV, 50 mV, and 20 mV, respectively, in the absence of calcium. They along with LRRC26 show distinct expression in different human tissues: LRRC26 and LRRC38 mainly in secretory glands, LRRC52 in testis, and LRRC55 in brain. LRRC26 and its paralogs are structurally and functionally distinct from the β-subunits and we designate them as a γ family of the BK channel auxiliary proteins, which potentially regulate the channel's gating properties over a spectrum of different tissues or cell types.

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Available from: Richard Aldrich, Sep 27, 2015
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    • "BK channels can co-assemble with modulatory auxiliary subunits BKβ 1-4 (Knaus et al., 1994a; Tanaka et al., 1997; Brenner et al., 2000a; Uebele et al., 2000), as well as a newly defined family of leucine-rich repeat containing subunits (LRRCs), referred to as γ subunits (Yan and Aldrich, 2010, 2012). Both BKβ and γ subunits contain sizeable extracellular regions and it is thought that these regions physically interact with the membrane-spanning domains of the BKα subunit. "
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    ABSTRACT: Large conductance, Ca 2+ -activated K + (BK) channels represent an important pathway for the outward flux of K + ions from the intracellular compartment in response to membrane depolarization, and/or an elevation in cytosolic free [Ca 2+ ]. They are functionally expressed in a range of mammalian tissues (e.g., nerve and smooth muscles), where they can either enhance or dampen membrane excitability. The diversity of BK channel activity results from the considerable alternative mRNA splicing and post-translational modification (e.g., phosphorylation) of key domains within the pore-forming α subunit of the channel complex. Most of these modifications are regulated by distinct upstream cell signaling pathways that influence the structure and/or gating properties of the holo-channel and ultimately, cellular function. The channel complex may also contain auxiliary subunits that further affect channel gating and behavior, often in a tissue-specific manner. Recent studies in human and animal models have provided strong evidence that abnormal BK channel expression/function contributes to a range of pathologies in nerve and smooth muscle. By targeting the upstream regulatory events modulating BK channel behavior, it may be possible to therapeutically intervene and alter BK channel expression/function in a beneficial manner.
    Frontiers in Physiology 08/2014; 5(316). DOI:10.3389/fphys.2014.00316 · 3.53 Impact Factor
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    • "The pore-forming α-subunits of large conductance calcium- and voltage- activated potassium (BK) channels are encoded by only a single gene, KCNMA1, yet these channels display considerable functional diversity to control an eclectic array of physiological processes in distinct cells and systems of the body (Salkoff et al., 2006; Contreras et al., 2013). Multiple mechanisms exist and work combinatorially to expand this physiological diversity including alternative pre-mRNA splicing of the α-subunit (Fodor and Aldrich, 2009), assembly with regulatory and accessory β- and γ- subunits (Orio et al., 2002; Yan and Aldrich, 2012) and post-translational modification via a diverse array of signaling pathways (Schubert and Nelson, 2001; Hou et al., 2009; Toro et al., 2013). These mechanisms ultimately control either the number of BK channels that are resident at a plasma membrane or affect the intrinsic properties or regulation of the channel at the membrane. "
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    ABSTRACT: Mechanisms that control surface expression and/or activity of large conductance calcium-activated potassium (BK) channels are important determinants of their (patho)physiological function. Indeed, BK channel dysfunction is associated with major human disorders ranging from epilepsy to hypertension and obesity. S-acylation (S-palmitoylation) represents a major reversible, post-translational modification controlling the properties and function of many proteins including ion channels. Recent evidence reveals that both pore-forming and regulatory subunits of BK channels are S-acylated and control channel trafficking and regulation by AGC-family protein kinases. The pore-forming α-subunit is S-acylated at two distinct sites within the N- and C-terminus, each site being regulated by different palmitoyl acyl transferases (zDHHCs) and acyl thioesterases (APTs). S-acylation of the N-terminus controls channel trafficking and surface expression whereas S-acylation of the C-terminal domain determines regulation of channel activity by AGC-family protein kinases. S-acylation of the regulatory β4-subunit controls ER exit and surface expression of BK channels but does not affect ion channel kinetics at the plasma membrane. Furthermore, a significant number of previously identified BK-channel interacting proteins have been shown, or are predicted to be, S-acylated. Thus, the BK channel multi-molecular signaling complex may be dynamically regulated by this fundamental post-translational modification and thus S-acylation likely represents an important determinant of BK channel physiology in health and disease.
    Frontiers in Physiology 08/2014; 5:281. DOI:10.3389/fphys.2014.00281 · 3.53 Impact Factor
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    • "Likewise, the γ2-subunit has been shown to modulate a BK Ca -related pH-sensitive channel (Slo3) in sperm (Yang et al., 2011). An extensive study by Yan and Aldrich (2012) showed that all four γ-subunits are expressed in the human uterus. This finding is intriguing because myometrial BK Ca channel activity is significantly higher in women at labor than in non-pregnant women; in fact, at labor, BK Ca activity is independent of intracellular Ca 2+ (Khan et al., 1993). "
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    ABSTRACT: The large-conductance voltage- and Ca(2+)-activated K(+) channel (BKCa) is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., β1- and β2-subunits), association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function.
    Frontiers in Physiology 07/2014; 5:289. DOI:10.3389/fphys.2014.00289 · 3.53 Impact Factor
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