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


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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    • "BK currents are produced by tetrameric assembly of four pore-forming a subunits, encoded by the Kcnma1 gene (Butler et al. 1993). BK current properties are modulated by several nonobligatory b (b1–4) and c accessory subunits (c1–4) (Brenner et al. 2000a; Yan and Aldrich 2012), tuning current properties for diverse roles across a variety of tissues. In rodents, BK channels are found in brain (Tseng-Crank et al. 1994; Kang et al. 1996; Smith et al. 2002; Faber and Sah 2003; Sausbier et al. 2004; Brenner et al. 2005; Girouard et al. 2010), peripheral neurons (Scholz et al. 1998; Ramanathan et al. 1999), muscle (Tseng-Crank et al. 1994; McCobb et al. 1995; Nelson et al. 1995; Heppner et al. 1997), and nonexcitable cells such as glia, kidney, bone, and endothelium (Morita et al. 1997; Papassotiriou et al. 2000; Ransom and Sontheimer 2001; Filosa et al. 2006; Henney et al. 2009; Li et al. 2009). "
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    ABSTRACT: BK large conductance calcium-activated K(+) channels (KC a1.1) are expressed widely across many tissues, contributing to systemic regulation of cardiovascular, neurological, and other specialized physiological functions. The pore-forming α subunit is encoded by the Kcnma1 gene, originally named mSlo1 in mouse and slowpoke in Drosophila. Global deletion in mouse (Kcnma1(-/-)) produces a plethora of defects in neuron and muscle excitability, as well as other phenotypes related to channel function in nonexcitable cells. While homozygous null mice are viable, the ubiquitous loss of BK function has complicated the interpretation of phenotypes involving the interaction of multiple cell types which independently express BK channels. Here, we report the generation of a targeted allele for conditional inactivation of Kcnma1 using the Cre-loxP system (Kcnma1(fl)-tdTomato). Cre-mediated recombination generates a null allele, and BK currents were not detectable in neurons and muscle cells from Nestin-Cre; Kcnma1(fl/fl) and SM22α-Cre; Kcnma1(fl/fl) mice, respectively. tdTomato expression was detected in Cre-expressing tissues, but not in Cre-negative controls. These data demonstrate the utility of Kcnma1(fl)-tdTomato for conditional deletion of the BK channel, facilitating the understanding of tissue-specific contributions to physiological function in vivo.
    11/2015; 3(11). DOI:10.14814/phy2.12612
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    • "Consistent with their predicted extracellular location, the LRR domains of the γ subunits all contain single or multiple consensus N-glycosylation sites: Asn-Xaa-Ser/Thr, where Xaa is not a proline . For the γ1 subunit, N147Q mutation and enzymatic removal of the N-linked glycan by PNGase F resulted in disappearance of an upper glycosylated-mass band in SDS-PAGE (Yan and Aldrich, 2012). "
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    ABSTRACT: The large-conductance, calcium- and voltage-activated potassium (BK) channel has the largest single-channel conductance among potassium channels and can be activated by both membrane depolarization and increases in intracellular calcium concentration. BK channels consist of pore-forming, voltage- and calcium-sensing α subunits, either alone or in association with regulatory subunits. BK channels are widely expressed in various tissues and cells including both excitable and non-excitable cells and display diverse biophysical and pharmacological characteristics. This diversity can be explained in part by posttranslational modifications and alternative splicing of the α subunit, which is encoded by a single gene, KCNMA1, as well as by tissue-specific β subunit modulation. Recently, a leucine-rich repeat-containing membrane protein, LRRC26, was found to interact with BK channels and cause an unprecedented large negative shift (~-140 mV) in the voltage dependence of the BK channel activation. LRRC26 allows BK channels to open even at near-physiological calcium concentration and membrane voltage in non-excitable cells. Three LRRC26-related proteins, LRRC52, LRRC55, and LRRC38, were subsequently identified as BK channel modulators. These LRRC proteins are structurally and functionally distinct from the BK channel β subunits and were designated as γ subunits. The discovery of the γ subunits adds a new dimension to BK channel regulation and improves our understanding of the physiological functions of BK channels in various tissues and cell types. Unlike BK channel β subunits, which have been intensively investigated both mechanistically and physiologically, our understanding of the γ subunits is very limited at this stage. This article reviews the structure, modulatory mechanisms, physiological relevance, and potential therapeutic implications of γ subunits as they are currently understood.
    Frontiers in Physiology 10/2014; 5:401. DOI:10.3389/fphys.2014.00401 · 3.53 Impact Factor
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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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