Cyclic nucleotide regulation of store-operated Ca2+ influx in airway smooth muscle

Binnaz Ay, Adeyemi Iyanoye, Gary C. Sieck, Y. S. Prakash, Christina M. Pabelick

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Sarcoplasmic reticulum (SR) Ca2+ release and plasma membrane Ca2+ influx are key to intracellular Ca2+ ([Ca 2+]i) regulation in airway smooth muscle (ASM). SR Ca 2+ 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 reintroduction of [Ca2+]o and characterized by several techniques. We examined cAMP effects on SOCC by activating SOCC in the presence of 1 μM isoproterenol or 100 μM dibutryl cAMP (cell-permeant cAMP analog), whereas we examined cGMP effects 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-bromoguanosine 3′,5′-cyclic monophosphate (cell-permeant cGMP analog). The role of protein kinases A and G was examined by preexposure to 100 nM KT-5720 and 500 nM KT-5823, 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., β-agonists vs. nitric oxide).

Original languageEnglish (US)
Pages (from-to)L278-L283
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number2
StatePublished - Feb 2006


  • Adenosine 3′,5′-cyclic monophosphate
  • Capacitative calcium entry
  • Guanosine 3′,5′-cyclic monophosphate
  • Isoproterenol
  • Nitric oxide
  • Trachea

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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