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ORAI and Store-Operated Calcium Influx in Human Airway Smooth Muscle Cells

¹ Division of Therapeutics and Molecular Medicine, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom

Correspondence and requests for reprints should be addressed to Ian P. Hall, DM, FRCP, Division of Therapeutics and Molecular Medicine, University of Nottingham, Queens Medical Centre, Nottingham, UK, NG7 2UH. E-mail: ian.hall{at}nottingham.ac.uk

The initial bronchoconstrictor response of the asthmatic airway depends on airway smooth muscle (ASM) contraction. Intracellular calcium is a key signaling molecule, mediating a number of responses, including proliferation, gene expression, and contraction of ASM. Ca²⁺ influx through receptor-operated calcium (ROC) or store-operated calcium (SOC) channels is believed to mediate longer term signals. The mechanisms of SOC activation in ASM remain to be elucidated. Recent literature has identified the STIM and ORAI proteins as key signaling players in the activation of the SOC subtype; calcium release–activated channel current (I_CRAC) in a number of inflammatory cell types. However, the role for these proteins in activation of SOC in smooth muscle is unclear. We have previously demonstrated a role for STIM1 in SOC channel activation in human ASM. The aim of this study was to investigate the expression and define the potential roles of the ORAI proteins in SOC-associated Ca²⁺ influx in human ASM cells. Here we show that knockdown of ORAI1 by siRNA resulted in reduced thapsigargin- or cyclopiazonic acid (CPA)–induced Ca²⁺ influx, without affecting Ca²⁺ release from stores or basal levels. CPA-induced inward currents were also reduced in the ORAI1 knockdown cells. We propose that ORAI1 together with STIM1 are important contributors to SOC entry in ASM cells. These data extend the major tissue types in which these proteins appear to be major determinants of SOC influx, and suggest that modulation of these pathways may prove useful in the treatment of bronchoconstriction.

Key Words: airway smooth muscle • ORAI • store-operated calcium entry • ion channels

CLINICAL RELEVANCE Our findings demonstrate expression and roles for ORAI homologs in store-operated calcium influx in human airway smooth muscle cells. Modulation of calcium influx pathways may prove useful in the treatment of bronchoconstriction in asthmatic airways.

 

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