Local Calcium Signaling in Airway Smooth Muscle Cells

Chapter

Abstract

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 (EK), 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 (ECl), 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.

Keywords

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

Abbreviation

ACh

Acetylcholine

AHR

Airway hyperresponsiveness

AP

Action potential

ASMC

Airway smooth muscle cell

BiMPT

Biphasic membrane potential transient

BK

Big-conductance Ca2+-activated K+ channel

Ca2+

Calcium

[Ca2+]i

Intracellular calcium concentration

cADPR

Cyclic ADP-ribose

CaMKII

Ca2+/calmodulin-dependent kinase II

CaN

Calcineurin

CICR

Calcium-induced calcium release

ClCa

Calcium-activated chloride channel

CRU

Calcium release unit

DAG

Diacylglycerol

ECl

Chloride equilibration potential

EGTA

Ethylene glycol tetraacetic acid

EK

Potassium equilibration potential

FKBP12/12.6

FK506 binding protein 12/12.6

IP3

Inositol 1,4,5-trisphosphate

IP3R

Inositol 1,4,5-trisphosphate receptor

M3R

Muscarinic type 3 receptor

mACH

Methacholine

PIP2

Phosphatidylinositol 4,5-bisphosphate

PKC

Protein kinase C

PLC

Phospholipase C

RyR

Ryanodine receptor

SR

Sarcoplasmic reticulum

STIC

Spontaneous transient inward current

STOC

Spontaneous transient outward current

STOIC

Spontaneous transient outward/inward currents

VDCC

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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