Bone Biomechanical Behavior in Adult Mice is Regulated by Osteoblast Gi Signaling in a Sex- and Site-Specific Manner

2011 ◽  
Author(s):  
Aaron J. Fields ◽  
Susan M. Millard ◽  
Jeannie F. Bailey ◽  
Dylan O’Carroll ◽  
Jeffrey C. Lotz ◽  
...  
Keyword(s):  
Bone Mass ◽  
Bone Strength ◽  
G Protein Coupled Receptors ◽  
Signaling Mechanism ◽  
Biomechanical Behavior ◽  
Adult Mice ◽  
Trabecular Microstructure ◽  
And Function ◽  
The Relationship ◽  
G Protein Coupled

Osteoporosis decreases bone strength owing to loss of bone mass and deterioration in bone microstructure. The maintenance of bone mass and microstructure depends, at least in part, on the signaling and function of osteoblasts. For example, Gi-coupled signaling by G-protein coupled receptors endogenous to osteoblasts has been shown to restrict cortical and trabecular bone formation in female mice [1,2]. This suggests that inhibiting Gi-coupled signaling in osteoblasts may be an effective strategy for the development of anabolic osteoporosis therapies. However, it remains unclear whether inhibiting Gi-coupled signaling improves bone biomechanical behavior. Thus, the objectives of this study were to: 1) quantify the effect of Gi-coupled signaling on bone strength and bone stiffness; and 2) determine the effects of this signaling mechanism on cortical and trabecular microstructure and on the relationship between mechanical behavior and microstructure.

scholarly journals Molecular Structure and Physiological Functions of GABAB Receptors

2004 ◽  
Vol 84 (3) ◽  
pp. 835-867 ◽  
Author(s):  
Bernhard Bettler ◽  
Klemens Kaupmann ◽  
Johannes Mosbacher ◽  
Martin Gassmann
Keyword(s):  
G Protein Coupled Receptors ◽  
Gabab Receptors ◽  
Rapid Progress ◽  
Molecular Tools ◽  
And Function ◽  
The Relationship ◽  
G Protein Coupled ◽  
Review Current ◽  
Made In ◽  
Surprising Discovery

GABAB receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABAB receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABAB system. This led to the surprising discovery that GABAB receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABAB receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABAB receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABAB receptor polymorphisms to epilepsy. Significantly, the cloning of GABAB receptors enabled identification of the first allosteric GABAB receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABAB receptors and discuss ongoing drug-discovery efforts.

The Mechanism and Function of Agonist-Induced Trafficking of G-protein Coupled Receptors

2000 ◽  
Vol 28 (3) ◽  
pp. A59-A59
Author(s):  
K. DeFea ◽  
O. Dery ◽  
F. Schmidlin ◽  
N.W. Bunnett
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
And Function ◽  
G Protein Coupled

scholarly journals Methods used to study the oligomeric structure of G-protein-coupled receptors

2017 ◽  
Vol 37 (2) ◽  
Author(s):  
Hui Guo ◽  
Su An ◽  
Richard Ward ◽  
Yang Yang ◽  
Ying Liu ◽  
...  
Keyword(s):  
Energy Transfer ◽  
G Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
G Protein Coupled Receptors ◽  
Experimental Techniques ◽  
Distribution Analysis ◽  
Wide Range ◽  
And Function ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs), which constitute the largest family of cell surface receptors, were originally thought to function as monomers, but are now recognized as being able to act in a wide range of oligomeric states and indeed, it is known that the oligomerization state of a GPCR can modulate its pharmacology and function. A number of experimental techniques have been devised to study GPCR oligomerization including those based upon traditional biochemistry such as blue-native PAGE (BN-PAGE), co-immunoprecipitation (Co-IP) and protein-fragment complementation assays (PCAs), those based upon resonance energy transfer, FRET, time-resolved FRET (TR-FRET), FRET spectrometry and bioluminescence resonance energy transfer (BRET). Those based upon microscopy such as FRAP, total internal reflection fluorescence microscopy (TIRFM), spatial intensity distribution analysis (SpIDA) and various single molecule imaging techniques. Finally with the solution of a growing number of crystal structures, X-ray crystallography must be acknowledged as an important source of discovery in this field. A different, but in many ways complementary approach to the use of more traditional experimental techniques, are those involving computational methods that possess obvious merit in the study of the dynamics of oligomer formation and function. Here, we summarize the latest developments that have been made in the methods used to study GPCR oligomerization and give an overview of their application.

scholarly journals Defining the roles of arrestin2 and arrestin3 in vasoconstrictor receptor desensitization in hypertension

2015 ◽  
Vol 309 (3) ◽  
pp. C179-C189 ◽  
Author(s):  
Jonathon M. Willets ◽  
Craig A. Nash ◽  
Richard D. Rainbow ◽  
Carl P. Nelson ◽  
R. A. John Challiss
Keyword(s):  
P2y Receptors ◽  
G Protein Coupled Receptors ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Spontaneously Hypertensive ◽  
Regulatory Changes ◽  
Wistar Kyoto ◽  
Arterial Constriction ◽  
And Function ◽  
G Protein Coupled

Prolonged vasoconstrictor-stimulated phospholipase C activity can induce arterial constriction, hypertension, and smooth muscle hypertrophy/hyperplasia. Arrestin proteins are recruited by agonist-occupied G protein-coupled receptors to terminate signaling and counteract changes in vascular tone. Here we determine whether the development of hypertension affects arrestin expression in resistance arteries and how such changes alter arterial contractile signaling and function. Arrestin2/3 expression was increased in mesenteric arteries of 12-wk-old spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) controls, while no differences in arrestin expression were observed between 6-wk-old SHR and WKY animals. In mesenteric artery myography experiments, high extracellular K+-stimulated contractions were increased in both 6- and 12-wk-old SHR animals. Concentration-response experiments for uridine 5′-triphosphate (UTP) acting through P2Y receptors displayed a leftward shift in 12-wk, but not 6-wk-old animals. Desensitization of UTP-stimulated vessel contractions was increased in 12-wk-old (but not 6-wk-old) SHR animals. Dual IP3/Ca2+ imaging in mesenteric arterial cells showed that desensitization of UTP and endothelin-1 (ET1) responses was enhanced in 12-wk-old (but not 6-wk-old) SHR compared with WKY rats. siRNA-mediated depletion of arrestin2 for UTP and arrestin3 for ET1, reversed the desensitization of PLC signaling. In conclusion, arrestin2 and 3 expression is elevated in resistance arteries during the emergence of the early hypertensive phenotype, which underlies an enhanced ability to desensitize vasoconstrictor signaling and vessel contraction. Such regulatory changes may act to compensate for increased vasoconstrictor-induced vessel contraction.

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