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1 Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Anesthesiology, Marmara University, Istanbul, Turkey
2 Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN, USA
3 Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA
4 Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: pabelick{at}mayo.edu.
Sarcoplasmic reticulum (SR) Ca2+ release and plasma membrane Ca2+ influx are key to intracellular Ca2+ ([Ca2+]i) regulation in airway smooth muscle (ASM). SR Ca2+ depletion triggers influx via store-operated Ca2+ channels (SOCC) for SR replenishment. Several clinically relevant bronchodilators mediate their effect via cyclic nucleotides (cAMP, cGMP). We examined the effect of cyclic nucleotides on SOCC-mediated Ca2+ influx in enzymatically-dissociated porcine ASM cells. SR Ca2+ was depleted by 1 µM cyclopiazonic acid in 0 extracellular Ca2+ ([Ca2+]o), nifedipine and KCl (preventing Ca2+ influx through L-type and SOCC channels). SOCC was then activated by re-introduction of [Ca2+]o, and characterized using several techniques. cAMP effects on SOCC were examined by activating SOCC in the presence of 1 µM isoproterenol or 100 µM dibutryl cAMP (cell permeant cAMP analog) while cGMP effects were examined using 1 µM (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO nitric oxide donor) or 100 µM 8-Br-cGMP (cell permeant cGMP analog). The role of protein kinases A and G were examined by pre-exposure to 100 nM KT5720 and 500 nM KT5823, respectively. SOCC-mediated Ca2+ influx was dependent on the extent of SR Ca2+ depletion, sensitive to Ni2+ and La3+, but not inhibitors of voltage-gated influx channels. cAMP as well as cGMP potently inhibited Ca2+ influx, predominantly via their respective protein kinases. Additionally, cAMP cross-activation of protein kinase G contributed to SOCC inhibition. These data demonstrate that a Ni2+/La3+-sensitive Ca2+ influx in ASM triggered by SR Ca2+ depletion is inhibited by cAMP and cGMP via a protein kinase mechanism. Such inhibition may play a role in the bronchodilatory response of ASM to clinically relevant drugs (e.g. 
-agonists vs. nitric oxide).
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