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...