Structural features of the inactive and active states of the melanin-concentrating hormone receptors: Insights from molecular simulations

2004 ◽  
Vol 56 (3) ◽  
pp. 430-448 ◽  
Author(s):  
Rosa Maria Vitale ◽  
Carlo Pedone ◽  
Pier G. De Benedetti ◽  
Francesca Fanelli
Keyword(s):  
Hormone Receptors ◽  
Molecular Simulations ◽  
Structural Features ◽  
Melanin Concentrating Hormone

scholarly journals Acute desensitization of phospholipase C-coupled muscarinic M3 receptors but not gonadotropin-releasing hormone receptors co-expressed in αT3-1 cells: implications for mechanisms of rapid desensitization

1998 ◽  
Vol 333 (2) ◽  
pp. 301-308 ◽  
Author(s):  
Gary B. WILLARS ◽  
Craig A. McARDLE ◽  
Stefan R. NAHORSKI
Keyword(s):  
Phospholipase C ◽  
Cell Line ◽  
Hormone Receptors ◽  
State Level ◽  
Structural Features ◽  
Gnrh Receptor ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
M3 Receptors ◽  
M3 Receptor

In the present study we have expressed the muscarinic M3 receptor in an immortalized mouse pituitary cell line (αT3-1), which expresses an endogenous gonadotropin-releasing hormone (GnRH) receptor, to examine potential differences in acute receptor regulation. Both of these receptors couple to the activation of phosphoinositide-specific phospholipase C (PLC) in these cells and we demonstrate that, despite expression in the same cell background, acute desensitization is a feature of muscarinic M3 receptors but not of GnRH receptors. We show that, when the concentrations of GnRH and methacholine are matched to give approximately equivalent maximal elevations of Ins(1,4,5)P3, the GnRH receptor is able to sustain PLC activity at the initial rate, whereas the muscarinic M3 receptor cannot. Thus PLC-activating G-protein-coupled receptors are able to undergo rapid desensitization in this cell line, indicating that the desensitization profile is receptor-specific rather than cell-specific. This argues strongly that post-receptor regulatory features do not have a prominent role in mediating rapid desensitization in these cells. Furthermore GnRH receptor-mediated PLC activity is sustained despite a marked and persistent depletion in the steady-state level of PtdIns(4,5)P2. In contrast, activation of muscarinic receptors is not sustained despite only a transient decrease in PtdIns(4,5)P2 concentration. Thus, whereas the contribution of PtdIns(4,5)P2 depletion to the temporal profile of receptor-mediated PLC signalling has been difficult to assess, the present results demonstrate that this is unlikely to be of importance in these cells. We suggest that unique structural features of the GnRH receptor result in a lack of appropriate regulatory phospho-acceptor sites and that the absence of agonist-dependent phosphorylation might underlie the lack of acute regulation.

Signalling pathway of goldfish melanin-concentrating hormone receptors 1 and 2

2011 ◽  
Vol 169 (1-3) ◽  
pp. 6-12 ◽  
Author(s):  
Akie Hamamoto ◽  
Kanta Mizusawa ◽  
Akiyoshi Takahashi ◽  
Yumiko Saito
Keyword(s):  
Hormone Receptors ◽  
Signalling Pathway ◽  
Melanin Concentrating Hormone

Molecular cloning and expression of two melanin-concentrating hormone receptors in goldfish

Peptides ◽  
2009 ◽  
Vol 30 (11) ◽  
pp. 1990-1996 ◽  
Author(s):  
Kanta Mizusawa ◽  
Yumiko Saito ◽  
Zhiwei Wang ◽  
Yuki Kobayashi ◽  
Kouhei Matsuda ◽  
...  
Keyword(s):  
Molecular Cloning ◽  
Hormone Receptors ◽  
Cloning And Expression ◽  
Melanin Concentrating Hormone

scholarly journals System among the corticosteroids: specificity and molecular dynamics

2011 ◽  
Vol 9 (66) ◽  
pp. 43-53 ◽  
Author(s):  
Jennifer C. Brookes ◽  
Mario D. Galigniana ◽  
Anthony H. Harker ◽  
A. Marshall Stoneham ◽  
Gavin P. Vinson
Keyword(s):  
Molecular Dynamics ◽  
Biological Activities ◽  
Molecular Simulations ◽  
Structural Features ◽  
Conformational Mobility ◽  
Receptor Interactions ◽  
Biological Specificity ◽  
Glucocorticoid Action

Understanding how structural features determine specific biological activities has often proved elusive. With over 161 000 steroid structures described, an algorithm able to predict activity from structural attributes would provide manifest benefits. Molecular simulations of a range of 35 corticosteroids show striking correlations between conformational mobility and biological specificity. Thus steroid ring A is important for glucocorticoid action, and is rigid in the most specific (and potent) examples, such as dexamethasone. By contrast, ring C conformation is important for the mineralocorticoids, and is rigid in aldosterone. Other steroids that are less specific, or have mixed functions, or none at all, are more flexible. One unexpected example is 11-deoxycorticosterone, which the methods predict (and our activity studies confirm) is not only a specific mineralocorticoid, but also has significant glucocorticoid activity. These methods may guide the design of new corticosteroid agonists and antagonists. They will also have application in other examples of ligand–receptor interactions.

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