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Identification of a new splice variant of large‐conductance Ca 2+ ‐activated K + (BK) channel α subunit from human chondrocyte
Author(s) -
Suzuki Yoshiaki,
Ohya Susumu,
Yamamura Hisao,
Giles Wayne R.,
Imaizumi Yuji
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.750.27
Subject(s) - bk channel , chemistry , histamine , microbiology and biotechnology , intracellular , chondrocyte , bradykinin , biophysics , membrane potential , biochemistry , biology , endocrinology , in vitro , receptor
Changes in intracellular calcium concentration ([Ca 2+ ] i ) modulate chondrogenesis, proliferation, cell death and baseline anabolic and catabolic activities in chondrocytes. Under pathophysiological conditions, like osteoarthritis (OA), histamine release from resident mast cells enhances the production of pro‐inflammatory mediators and the activities of matrix degrading enzymes. Specific patterns of [Ca 2+ ] i changes are considered as essential components initiating and/or progressing the disease. In an established model cell‐line of the human chondrocyte, OUMS‐27 cells, large‐conductance Ca 2+ ‐activated K + (BK) channels are involved in the enhancement of histamine‐induced Ca 2+ influx by the activation of Ca 2+ release‐activated Ca 2+ (CRAC) channels consisting of Orai1‐Orai2 heteromers and STIM1 via the modulation of membrane potential. We have identified a novel BKα splice variant (BKαΔe2) in OUMS‐27 cells. Although BKαΔe2 lacks exon2 that codes the intracellular S0–S1 linker (Glu127‐Leu180), significant expression was detected in several human tissues including chondrocytes of OA patients and in mouse tissues as well. BKαΔe2 channels are not expressed on plasma membrane (PM), but can traffic to PM after forming hetero‐tetramer units with wild‐type BKα (BKαWT). These hetero‐tetramers of BKα have a smaller single channel conductance and exhibit lower trafficking efficiency than BKαWT homo‐tetramers in a stoichiometry‐dependent manner. BKαΔe2 knockdown in OUMS‐27 chondrocytes increased BK current density, and augmented the responsiveness to histamine assayed as cyclooxygenase‐2 gene expression. These findings provide significant new evidence that BKαΔe2 can modulate cellular responses to physiological stimuli in human chondrocyte and contribute under pathophysiological conditions, such as OA. Support or Funding Information This work was supported by JSPS KAKENHI Grant Numbers, 26293021 and 15H01408 to Y.I., 26860059, 16H06215 and 16K15127 to Y.S., 16K08278 to H.Y. This work was also supported by a Grant‐in‐Aid from Takeda Science Foundation (to Y.S.) and Salt Science Research Foundation [Grant 1637] (to Y.S.). W.G. holds an Alberta Innovates‐Health Solutions Scientist Award, and CIHR funding. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .