Calcium Signaling in Airway Smooth Muscle Remodeling

Chapter

Abstract

Asthma is characterized by airway remodeling. One of the most important manifestations of airway remodeling is an increased mass of airway smooth muscle cells (ASMCs), which is mainly due to hyperplasia (increased cell number). Hyperplasia can result from an increase in cell proliferation, an increase in migration, or a decrease in cell apoptosis. Understanding of the mechanisms underlying ASMC remodeling may give rise to novel avenues for the therapy of asthma and other respiratory diseases. Recent studies from our group and others suggest that Ca2+ signaling is important in airway remodeling. Gene and protein expression of Ca2+ pump sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) has been shown to be reduced in ASMCs from patients with moderately severe asthma. Conversely, transient receptor potential canonical 3 (TRPC3) channel expression and activity are significantly increased in asthmatic ASMCs, resulting in increased extracellular Ca2+ influx, activation of the protein tyrosine kinase 2 (PTK2)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/calcineurin signaling axis, increased cyclin D1 transcription and proliferation, and, ultimately, airway remodeling. Orai1-encoded Ca2+-release-activated Ca2+ (CRAC) channels and stromal interacting molecule 1 (STIM1) also appear to participate in mediating platelet-derived grow factor (PDGF)-dependent store-operated Ca2+ entry (SOCE) and the proliferation and migration of ASMCs in asthma. This increased Ca2+ signaling may augment the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) to phosphorylate cyclic adenosine monophosphate (cAMP) response element binding (CREB) and activate various genes that regulate the cell cycle, thereby leading to asthmatic airway remodeling. Airway remodeling may also be associated with an increased size of ASMCs (hypertrophy). This cellular response is mediated by phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/eukaryotic translation initiation factor 4E (eIF-4F), ribosomal S6 kinase (RSK)/S6-related kinase, and glycogen synthase kinase 3β (GSK3β) signaling pathways, all of which are Ca2+ dependent. Evidently, continual studies in the field will significantly improve our current knowledge regarding the molecular mechanisms of asthma and other airway disorders.

Keywords

TRPC3 channels Calcium signaling NF-κB Airway remodeling Asthma 

Abbreviations

4E-BP

4E-binding protein

Ach

Acetylcholine

ASM

Airway smooth muscle

ASMC

ASM cell

CaM

Calmodulin

CaMK

Ca2+/CaM-dependent kinase

cAMP

Cyclic adenosine monophosphate

CICR

Ca2+-induced Ca2+ release

CRAC

Ca2+-release-activated Ca2+

CREB

cAMP response element binding

DAG

Diacylglycerol

EGR1

Early growth response protein 1

eIF2B

Eukaryotic translation initiation factor 2B

eIF-4F

Eukaryotic translation initiation factor 4E

ERK

Extracellular signal-regulated kinase

GPCR

G-protein-coupled receptor

GSK

Glycogen synthase kinase

IP3

Inositol trisphosphate

IP3R

IP3 receptor

[Ca2+]i

Intracellular Ca2+ concentration

JNK2

C-Jun amino-terminal kinase 2

mACH

Methacholine

M3AChR

Muscarinic M3 acetylcholine receptor

MKP1

Mitogen-activated protein kinases phosphatase 1

mTOR

Mammalian target of rapamycin

NFAT

Nuclear factor of activated T-cells

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NSCC

Nonselective cation channel

PAI1

Plasminogen activator inhibitor-1

PDGF

Platelet-derived growth factor

PI3K

Phosphoinositide 3-kinase

PIP2

Phosphatidylinositol 4, 5-bisphosphate

RSK

Ribosomal S6 kinase

RyR

Ryanodine receptor

SERCA

Sarco/endoplasmic reticulum Ca2+ ATPase

SOCC

Store-operated Ca2+ channel

SOCE

Store-operated Ca2+ entry

SR

Sarcoplasmic reticulum

STIM

Stromal interacting molecule

TRPC

Transient receptor potential canonical

VDCC

Voltage-dependent Ca2+ channel

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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Center for Cardiovascular Sciences (MC-8)Albany Medical CollegeAlbanyUSA

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