Local Calcium Signaling in Airway Smooth Muscle Cells

  • Qing-Hua LiuEmail author
  • Carlo Savoia
  • Yong-Xiao Wang
  • Yun-Min ZhengEmail author


Potentially fatal asthma attacks may result from airway hyperresponsiveness (AHR), which is the exaggerated contractile response of airway smooth muscle cells (ASMCs) to nonspecific stimuli. A better understanding of Ca2+ signaling in ASMC contraction can help develop advanced therapeutics for asthma. A common elementary form of Ca2+ signaling is the Ca2+ spark (i.e., a local transient Ca2+ release event). Ca2+ sparks occur as a result of the coordinated opening of a cluster of ryanodine receptors (RyRs) and play a fundamental role in skeletal, cardiac, and smooth muscle cells. This chapter summarizes the recent advances from our work and that of others in studies of Ca2+ sparks in ASMCs. Ca2+ sparks have been observed in equine, porcine, guinea-pig, and mouse ASMCs. Classical parasympathetic stimulation or membrane depolarization will activate native Gq protein-coupled muscarinic M3 receptors (M3Rs) and phospholipase C (PLC), generating inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP2) in ASMCs. IP3 will activate IP3 receptors (IP3Rs), inducing Ca2+ release, which may locally induce further Ca2+ release from RyR2, increasing Ca2+ sparks and associated contraction. Meanwhile, DAG activates protein kinase C-ε (PKCε), which inhibits Ca2+ sparks and contraction through RyR1. Calcineurin (CaN) promotes Ca2+ sparks and contraction through RyR1, in contrast to the role of PKCε. In ASMCs, basal Ca2+ sparks directly mediate a contractile force, as seen during RyR activation. These local Ca2+ events are also capable of regulating membrane potential through spontaneous transient inward currents (STICs) and spontaneous transient outward currents (STOCs). At rest with the membrane potential closer to K+ equilibrium potential (E K), Ca2+ sparks will preferentially activate TMEM16A-encoded Ca2+-activated Cl channels, depolarizing the cell membrane and promoting contraction. As the membrane potential rises closer to Cl equilibrium potential (E Cl), Ca2+ sparks will begin to activate big-conductance Ca2+-activated K+ (BK) channels, leading to cell hyperpolarization and preventing contraction. A disruption in this balancing of cell excitability could play a role in asthmatic AHR. During asthma, Ca2+ sparks, TMEM16A expression, and STICs are increased, providing a mechanistic setting for AHR, whereas the STOC pathway cannot maintain balance and a lower level of cell excitability, resulting in excessive contraction. Therefore, Ca2+ sparks and the associated signaling axis in ASMCs may become new and effective targets for asthma therapeutics.


Ca2+ sparks Ryanodine receptor Inositol 1,4,5-trisphosphate receptor Protein kinase C-ε, calcineurin Spontaneous transient outward current Spontaneous transient inward current 





Airway hyperresponsiveness


Action potential


Airway smooth muscle cell


Biphasic membrane potential transient


Big-conductance Ca2+-activated K+ channel




Intracellular calcium concentration


Cyclic ADP-ribose


Ca2+/calmodulin-dependent kinase II




Calcium-induced calcium release


Calcium-activated chloride channel


Calcium release unit




Chloride equilibration potential


Ethylene glycol tetraacetic acid


Potassium equilibration potential


FK506 binding protein 12/12.6


Inositol 1,4,5-trisphosphate


Inositol 1,4,5-trisphosphate receptor


Muscarinic type 3 receptor




Phosphatidylinositol 4,5-bisphosphate


Protein kinase C


Phospholipase C


Ryanodine receptor


Sarcoplasmic reticulum


Spontaneous transient inward current


Spontaneous transient outward current


Spontaneous transient outward/inward currents


Voltage-dependent calcium channel


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Institute for Medical Biology, College of Life SciencesSouth-Central University for NationalitiesWuhanChina
  2. 2.Center for Cardiovascular Sciences (MC-8)Albany Medical CollegeAlbanyUSA

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