PMID- 21278382
OWN - NLM
STAT- MEDLINE
DCOM- 20110601
LR  - 20220321
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 13
DP  - 2011 Apr 1
TI  - Beta-agonist-associated reduction in RGS5 expression promotes airway smooth 
      muscle hyper-responsiveness.
PG  - 11444-55
LID - 10.1074/jbc.M110.212480 [doi]
AB  - Although short-acting and long-acting inhaled beta(2)-adrenergic receptor agonists 
      (SABA and LABA, respectively) relieve asthma symptoms, use of either agent alone 
      without concomitant anti-inflammatory drugs (corticosteroids) may increase the 
      risk of disease exacerbation in some patients. We found previously that 
      pretreatment of human precision-cut lung slices (PCLS) with SABA impaired 
      subsequent beta(2)-agonist-induced bronchodilation, which occurred independently of 
      changes in receptor quantities. Here we provide evidence that prolonged exposure 
      of cultured human airway smooth muscle (HuASM) cells to beta(2)-agonists directly 
      augments procontractile signaling pathways elicited by several compounds 
      including thrombin, bradykinin, and histamine. Such treatment did not increase 
      surface receptor amounts or expression of G proteins and downstream effectors 
      (phospholipase Cbeta and myosin light chain). In contrast, beta-agonists decreased 
      expression of regulator of G protein signaling 5 (RGS5), which is an inhibitor of 
      G-protein-coupled receptor (GPCR) activity. RGS5 knockdown in HuASM increased 
      agonist-evoked intracellular calcium flux and myosin light chain (MLC) 
      phosphorylation, which are prerequisites for contraction. PCLS from Rgs5(-/-) 
      mice contracted more to carbachol than those from WT mice, indicating that RGS5 
      negatively regulates bronchial smooth muscle contraction. Repetitive beta(2)-agonist 
      use may not only lead to reduced bronchoprotection but also to sensitization of 
      excitation-contraction signaling pathways as a result of reduced RGS5 expression.
FAU - Yang, Zhao
AU  - Yang Z
AD  - Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID, 
      National Institutes of Health, Bethesda, Maryland 20892, USA.
FAU - Cooper, Philip R
AU  - Cooper PR
FAU - Damera, Gautam
AU  - Damera G
FAU - Mukhopadhyay, Indranil
AU  - Mukhopadhyay I
FAU - Cho, Hyeseon
AU  - Cho H
FAU - Kehrl, John H
AU  - Kehrl JH
FAU - Panettieri, Reynold A Jr
AU  - Panettieri RA Jr
FAU - Druey, Kirk M
AU  - Druey KM
LA  - eng
GR  - Z01 AI000939/Intramural NIH HHS/United States
GR  - HL5452235/HL/NHLBI NIH HHS/United States
GR  - HL544157/HL/NHLBI NIH HHS/United States
GR  - HL543102/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20110129
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adrenergic beta-2 Receptor Agonists)
RN  - 0 (Myosin Light Chains)
RN  - 0 (RGS Proteins)
RN  - 0 (RGS5 protein, human)
RN  - 0 (Rgs5 protein, mouse)
SB  - IM
MH  - Adrenergic beta-2 Receptor Agonists/*pharmacology
MH  - Animals
MH  - Gene Expression Regulation/*drug effects
MH  - HEK293 Cells
MH  - Humans
MH  - Lung/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Muscle Contraction/drug effects
MH  - Muscle, Smooth/*metabolism
MH  - Myocytes, Smooth Muscle/*metabolism
MH  - Myosin Light Chains/genetics/metabolism
MH  - Phosphorylation/drug effects
MH  - RGS Proteins/*biosynthesis/genetics
MH  - Signal Transduction/*drug effects/physiology
PMC - PMC3064200
EDAT- 2011/02/01 06:00
MHDA- 2011/06/02 06:00
PMCR- 2012/04/01
CRDT- 2011/02/01 06:00
PHST- 2011/02/01 06:00 [entrez]
PHST- 2011/02/01 06:00 [pubmed]
PHST- 2011/06/02 06:00 [medline]
PHST- 2012/04/01 00:00 [pmc-release]
AID - S0021-9258(20)53767-8 [pii]
AID - M110.212480 [pii]
AID - 10.1074/jbc.M110.212480 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 Apr 1;286(13):11444-55. doi: 10.1074/jbc.M110.212480. Epub 2011 
      Jan 29.