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Role of RhoA/Rho-kinase and Calcium Sensitivity in Airway Smooth Muscle Functions

  • Satoru ItoEmail author
Chapter

Abstract

Changes in the contractility of airway smooth muscle (ASM) play important roles in bronchoconstriction and airway hyperresponsiveness associated with the pathophysiology of asthma and possibly, in part, chronic obstructive pulmonary disease (COPD). A common feature associated with ASM contraction is phosphorylation of myosin light chain (MLC), which is determined by the balance between MLC kinase (MLCK) and MLC phosphatase (MLCP) activities. MLCK is activated by increases in the intracellular Ca2+ concentration ([Ca2+]i), whereas MLCP is inactivated by Rho-kinase, a target protein of RhoA, independently of [Ca2+]i. The latter mechanism, contraction due to MLCP inhibition mediated by RhoA/Rho-kinase, is a major type of Ca2+ sensitization. Phosphorylation of the 17-kD myosin phosphatase inhibitor protein by protein kinase C is another mechanism of Ca2+ sensitization via MLCP suppression. This chapter focuses on recent evidence regarding regulation of ASM contraction by the RhoA/Rho-kinase pathway and the possible roles of this pathway in the pathogenesis of asthma and COPD.

Keywords

Asthma Chronic obstructive pulmonary disease Ca2+ sensitization RhoA Rho-kinase Myosin light chain phosphatase 

Abbreviations

ASM

airway smooth muscle

[Ca2+]i

intracellular Ca2+ concentration

COPD

chronic obstructive pulmonary disease

CPI-17

17-kD myosin phosphatase inhibitor protein

GAP

GTPase-activating protein

GDI

guanine nucleotide dissociation inhibitor

GDP

guanosine diphosphate

GEF

guanine nucleotide exchange factor

G protein

GTP-binding protein

GTP

guanosine trisphosphate

IL

interleukin

IP3

inositol 1,4,5-trisphosphate

MBS

myosin-binding subunit

MLC

myosin light chain

MLCK

myosin light chain kinase

MLCP

myosin light chain phosphatase

PDGF

platelet-derived growth factor

PKA

protein kinase A

PKC

protein kinase C

Ser

serine

S1P

sphingosine 1-phosphate

SR

sarcoplasmic reticulum

Thr

threonine

TNF-α

tumor necrosis factor-α

TRP

transient receptor potential

Notes

Acknowledgments

This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (17790531, 19689017, and 22590837). We also thank Ms. Katherine Ono for providing language help.

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© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of Respiratory MedicineNagoya University Graduate School of MedicineNagoyaJapan

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