Extrasynaptic Localization of Inactivating Calcium-Activated Potassium Channels in Mouse Inner Hair Cells

Pyott, Sonja J.; Glowatzki, Elisabeth; Trimmer, James S.; Aldrich, Richard W.

doi:10.1523/jneurosci.3162-04.2004

Cited by 76 publications

(101 citation statements)

References 23 publications

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“…These cells are, in fact, epithelial-derived cells (42). In such cells, with 0 cytosolic Ca 2+ , BK currents are activated at very negative potentials relative to other BK currents (43,44), very similar to currents produced by the presence of LRRC26. Although this possibility will require further attention, we were unable to obtain any indication of Lrrc26 message in the cochlea.…”

Section: Discussionmentioning

confidence: 91%

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Yang

González-Pérez

Mukaibo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Leucine-rich-repeat-containing protein 26 (LRRC26) is the regulatory γ1 subunit of Ca 2+ -and voltage-dependent BK-type K + channels. BK channels that contain LRRC26 subunits are active near normal resting potentials even without Ca 2+ , suggesting they play unique physiological roles, likely limited to very specific cell types and cellular functions. By using Lrrc26 KO mice with a β-gal reporter, Lrrc26 promoter activity is found in secretory epithelial cells, especially acinar epithelial cells in lacrimal and salivary glands, and also goblet and Paneth cells in intestine and colon, although absent from neurons. We establish the presence of LRRC26 protein in eight secretory tissues or tissues with significant secretory epithelium and show that LRRC26 protein coassembles with the pore-forming BK α-subunit in at least three tissues: lacrimal gland, parotid gland, and colon. In lacrimal, parotid, and submandibular gland acinar cells, LRRC26 KO shifts BK gating to be like α-subunit-only BK channels. Finally, LRRC26 KO mimics the effect of SLO1/BK KO in reducing [K + ] in saliva. LRRC26-containing BK channels are competent to contribute to resting K + efflux at normal cell membrane potentials with resting cytosolic Ca 2+ concentrations and likely play a critical physiological role in supporting normal secretory function in all secretory epithelial cells.L arge-conductance, voltage-and Ca 2+ -regulated BK-type channels are widely expressed proteins, found not only in excitable cells, such as neurons, muscle, and endocrine cells, but also nonexcitable cells, including salivary (1) and lacrimal gland (2) acinar cells, and colonic crypt cells (3). Given the almost ubiquitous expression of BK channels among cells that play quite distinct physiological roles, it is particularly important to define the specific properties of BK channels in a given cell type and determine what the specific physiological role played by BK channels in a given cell may be. A hallmark of BK channels is their dual regulation by both membrane voltage and cytosolic Ca 2+ (4), both properties embedded within the tetramer of pore-forming α-subunits of each BK channel (5). However, the specific range of voltages over which a BK channel is active at a given Ca 2+ concentration is markedly dependent on the identity of regulatory subunits that can coassemble with the α-subunit in the mature channel complex. Of the two families of known BK regulatory subunits, β (6-11) and γ (12-14), an important feature of many of these subunits is the ability to shift the range of activation voltages at a given Ca 2+ . Although there is growing information about the loci of expression and functional roles of BK channels containing specific β-subunits (15), much less is known about those BK channels containing the γ1 (LRRC26, leucine-rich-repeat-containing subunit 26) subunit. However, LRRC26 is particularly fascinating because it causes the largest shift in BK gating (approximately −120 mV) of any known non-pore-forming regulatory subunit, resulting in BK channels that...

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Section: Discussionmentioning

confidence: 91%

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Yang

González-Pérez

Mukaibo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The mouse monoclonal antibody against the BK␣ subunit was graciously provided by Dr. James S. Trimmer (University of California, Davis) and used at a final concentration of 10 g/ml as described previously (20). The rabbit polyclonal antibody against the BK␣ subunit (APC-021) was purchased from Alomone Laboratories (Jerusalem, Israel) and diluted 1:500.…”

Section: Generation Of Transgenic Mice-slomentioning

confidence: 99%

“…IHCs express a potassium current (termed I K,f ) pharmacologically similar to BK currents, showing sensitivity to low concentrations of tetraethylammonium, charybdotoxin, and iberiotoxin (17)(18)(19)(20)(21). The transcript for the BK␣ subunit has been detected in IHCs (22,23), and immunostaining has verified expression of the BK␣ subunit in IHCs (17,20,21,24). Additionally, transcripts for both the BK␤1 and ␤4 subunit have been identified in IHCs (22).…”

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confidence: 99%

“…Unlike nonmammalian hair cells, IHCs are extrinsically tuned by accessory structures of the cochlea (9), the BK current found in IHCs does not require external calcium for activation (18,25,26), and BK channels in IHCs are extrasynaptic (20). Nevertheless, the importance of BK channels for the expression of mammalian hearing has been suggested indirectly in mice: I K,f becomes expressed in mouse IHCs at the onset of hearing (approximately 2 weeks postnatal (19)), and mice lacking the thyroid hormone receptor ␤ show delayed acquisition of I K,f by the IHCs and dramatically elevated auditory thresholds (27).…”

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confidence: 99%

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Cochlear Function in Mice Lacking the BK Channel α, β1, or β4 Subunits

Pyott

Meredith

Fodor

et al. 2007

Journal of Biological Chemistry

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Large conductance voltage-and calcium-activated potassium (BK) channels are important for regulating many essential cellular functions, from neuronal action potential shape and firing rate to smooth muscle contractility. In amphibians, reptiles, and birds, BK channels mediate the intrinsic frequency tuning of the cochlear hair cell by an electrical resonance mechanism. In contrast, inner hair cells of the mammalian cochlea are extrinsically tuned by accessory structures of the cochlea. Nevertheless, BK channels are present in inner hair cells and encode a fast activating outward current. To understand the role of the BK channel ␣ and ␤ subunits in mammalian inner hair cells, we analyzed the morphology, physiology, and function of these cells from mice lacking the BK channel ␣ (Slo ؊/؊ ) and also the ␤1 and ␤4 subunits (␤1/4 ؊/؊ ). ␤1/4 ؊/؊ mice showed normal subcellular localization, developmental acquisition, and expression of BK channels. ␤1/4 ؊/؊ mice showed normal cochlear function as indicated by normal auditory brainstem responses and distortion product otoacoustic emissions. Slo ؊/؊ mice also showed normal cochlear function despite the absence of the BK␣ subunit and the absence of fast activating outward current from the inner hair cells. Moreover, microarray analyses revealed no compensatory changes in transcripts encoding ion channels or transporters in the cochlea from Slo ؊/؊ mice. Slo ؊/؊ mice did, however, show increased resistance to noise-induced hearing loss. These findings reveal the fundamentally different contribution of BK channels to nonmammalian and mammalian hearing and suggest that BK channels should be considered a target in the prevention of noise-induced hearing loss.

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“…Previous studies have shown that several contributory conductances emerge and disappear in developing hair cells to culminate in the cessation of SAP. The functional expression of low voltage-activated K ϩ currents (I K,n ) derived from K v 7.4 channels and Ca 2ϩ -activated K ϩ currents at later stages of development clamps the membrane potential close to the reversal potential of K ϩ (2,3,9,10). Additionally, a reduction in the Ca 2ϩ current density and the late-stage disappearance of low voltage-activated Ca 2ϩ current (4) both contribute toward the transition from SAPs to graded receptor potentials, yet the underlying mechanisms for the latestage functional appearance of K ϩ currents are unknown, despite evidence to demonstrate that K ϩ channel genes and products are expressed several days prior to hair cell maturation (11,12).…”

mentioning

confidence: 99%

Plasticity in Membrane Cholesterol Contributes toward Electrical Maturation of Hearing

Levic

Yamoah

2011

Journal of Biological Chemistry

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Extrasynaptic Localization of Inactivating Calcium-Activated Potassium Channels in Mouse Inner Hair Cells

Cited by 76 publications

References 23 publications

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Cochlear Function in Mice Lacking the BK Channel α, β1, or β4 Subunits

Plasticity in Membrane Cholesterol Contributes toward Electrical Maturation of Hearing

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