Influence of Spacer–Receptor Interactions on the Stability of Bivalent Ligand–Receptor Complexes

2012 ◽  
Vol 116 (8) ◽  
pp. 2595-2604 ◽  
Author(s):  
Jorge Numata ◽  
Alok Juneja ◽  
Dennis J. Diestler ◽  
Ernst-Walter Knapp
Keyword(s):  
Bivalent Ligand ◽  
Receptor Complexes ◽  
Receptor Interactions ◽  
The Stability

scholarly journals Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Md Al Rahim ◽  
Yonejung Yoon ◽  
Christina Dimovasili ◽  
Zhiping Shao ◽  
Qian Huang ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
De Novo ◽  
Neuronal Damage ◽  
Trophic Factors ◽  
Presenilin 1 ◽  
Wild Type ◽  
Receptor Complexes ◽  
Aspartate Receptor ◽  
Familial Alzheimer Disease ◽  
The Stability

Abstract Excitotoxicity is thought to play key roles in brain neurodegeneration and stroke. Here we show that neuroprotection against excitotoxicity by trophic factors EFNB1 and brain-derived neurotrophic factor (called here factors) requires de novo formation of ‘survival complexes’ which are factor-stimulated complexes of N-methyl-d-aspartate receptor with factor receptor and presenilin 1. Absence of presenilin 1 reduces the formation of survival complexes and abolishes neuroprotection. EPH receptor B2- and N-methyl-d-aspartate receptor-derived peptides designed to disrupt formation of survival complexes also decrease the factor-stimulated neuroprotection. Strikingly, factor-dependent neuroprotection and levels of the de novo factor-stimulated survival complexes decrease dramatically in neurons expressing presenilin 1 familial Alzheimer disease mutants. Mouse neurons and brains expressing presenilin 1 familial Alzheimer disease mutants contain increased amounts of constitutive presenilin 1–N-methyl-d-aspartate receptor complexes unresponsive to factors. Interestingly, the stability of the familial Alzheimer disease presenilin 1–N-methyl-d-aspartate receptor complexes differs from that of wild type complexes and neurons of mutant-expressing brains are more vulnerable to cerebral ischaemia than neurons of wild type brains. Furthermore, N-methyl-d-aspartate receptor-mediated excitatory post-synaptic currents at CA1 synapses are altered by presenilin 1 familial Alzheimer disease mutants. Importantly, high levels of presenilin 1–N-methyl-d-aspartate receptor complexes are also found in post-mortem brains of Alzheimer disease patients expressing presenilin 1 familial Alzheimer disease mutants. Together, our data identify a novel presenilin 1-dependent neuroprotective mechanism against excitotoxicity and indicate a pathway by which presenilin 1 familial Alzheimer disease mutants decrease factor-depended neuroprotection against excitotoxicity and ischaemia in the absence of Alzheimer disease neuropathological hallmarks which may form downstream of neuronal damage. These findings have implications for the pathogenic effects of familial Alzheimer disease mutants and therapeutic strategies.

scholarly journals Identification of a Ser/Thr cluster in the C-terminal domain of the human prostaglandin receptor EP4 that is essential for agonist-induced beta-arrestin1 recruitment but differs from the apparent principal phosphorylation site

2004 ◽  
Vol 379 (3) ◽  
pp. 573-585 ◽  
Author(s):  
Frank NEUSCHÄFER-RUBE ◽  
Ricardo HERMOSILLA ◽  
Mathias REHWALD ◽  
Lars RÖNNSTRAND ◽  
Ralf SCHÜLEIN ◽  
...  
Keyword(s):  
G Protein ◽  
Phosphorylation Site ◽  
Receptor Subtype ◽  
Receptor Complexes ◽  
Prostaglandin Receptor ◽  
Terminal Domain ◽  
Prostaglandin E2 Receptor ◽  
The Stability ◽  
Necessary And Sufficient ◽  
G Protein Coupled

hEP4-R (human prostaglandin E2 receptor, subtype EP4) is a Gs-linked heterotrimeric GPCR (G-protein-coupled receptor). It undergoes agonist-induced desensitization and internalization that depend on the presence of its C-terminal domain. Desensitization and internalization of GPCRs are often linked to agonist-induced β-arrestin complex formation, which is stabilized by phosphorylation. Subsequently β-arrestin uncouples the receptor from its G-protein and links it to the endocytotic machinery. The C-terminal domain of hEP4-R contains 38 Ser/Thr residues that represent potential phosphorylation sites. The present study aimed to analyse the relevance of these Ser/Thr residues for agonist-induced phosphorylation, interaction with β-arrestin and internalization. In response to agonist treatment, hEP4-R was phosphorylated. By analysis of proteolytic phosphopeptides of the wild-type receptor and mutants in which groups of Ser/Thr residues had been replaced by Ala, the principal phosphorylation site was mapped to a Ser/Thr-containing region comprising residues 370–382, the presence of which was necessary and sufficient to obtain full agonist-induced phosphorylation. A cluster of Ser/Thr residues (Ser-389–Ser-390–Thr-391–Ser-392) distal to this site, but not the principal phosphorylation site, was essential to allow agonist-induced recruitment of β-arrestin1. However, phosphorylation greatly enhanced the stability of the β-arrestin1–receptor complexes. For maximal agonist-induced internalization, phosphorylation of the principal phosphorylation site was not required, but both β-arrestin1 recruitment and the presence of Ser/Thr residues in the distal half of the C-terminal domain were necessary.

scholarly journals Endosomal receptor kinetics determine the stability of intracellular growth factor signalling complexes

2007 ◽  
Vol 402 (3) ◽  
pp. 537-549 ◽  
Author(s):  
A. Rami Tzafriri ◽  
Elazer R. Edelman
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Dissociation Constant ◽  
Specific Binding ◽  
Ph Dependence ◽  
Growth Factor Receptor ◽  
Factor Binding ◽  
Receptor Complexes ◽  
Growth Factor Signalling ◽  
The Stability

There is an emerging paradigm that growth factor signalling continues in the endosome and that cell response to a growth factor is defined by the integration of cell surface and endosomal events. As activated receptors in the endosome are exposed to a different set of binding partners, they probably elicit differential signals compared with when they are at the cell surface. As such, complete appreciation of growth factor signalling requires understanding of growth factor–receptor binding and trafficking kinetics both at the cell surface and in endosomes. Growth factor binding to surface receptors is well characterized, and endosomal binding is assumed to follow surface kinetics if one accounts for changes in pH. Yet, specific binding kinetics within the endosome has not been examined in detail. To parse the factors governing the binding state of endosomal receptors we analysed a whole-cell mathematical model of epidermal growth factor receptor trafficking and binding. We discovered that the stability of growth factor–receptor complexes within endosomes is governed by three primary independent factors: the endosomal dissociation constant, total endosomal volume and the number of endosomal receptors. These factors were combined into a single dimensionless parameter that determines the endosomal binding state of the growth factor–receptor complex and can distinguish different growth factors from each other and different cell states. Our findings indicate that growth factor binding within endosomal compartments cannot be appreciated solely on the basis of the pH-dependence of the dissociation constant and that the concentration of receptors in the endosomal compartment must also be considered.

A theoretical study of complexes between fullerenes and concave receptors with interest in photovoltaics

2017 ◽  
Vol 19 (39) ◽  
pp. 26787-26798 ◽  
Author(s):  
E. M. Cabaleiro-Lago ◽  
J. Rodríguez-Otero ◽  
J. A. Carrazana-García
Keyword(s):  
Charge Transfer ◽  
Theoretical Study ◽  
Receptor Complexes ◽  
Transfer Capability ◽  
The Stability

The proper combination of host and guest allows controlling the stability and charge transfer capability of fullerene–concave receptor complexes.

The interaction of sialidase-treated hCG with ovarian cellular membranes

1981 ◽  
Vol 97 (2) ◽  
pp. 270-280 ◽  
Author(s):  
E. C. Brand ◽  
J. Odink ◽  
G. Klok ◽  
E. V. van Hall
Keyword(s):  
Binding Sites ◽  
Association Constant ◽  
Apparent Difference ◽  
Receptor Complexes ◽  
Number Of Binding Sites ◽  
Biological Potency ◽  
The Difference ◽  
The Stability ◽  
Dissociation Curves ◽  
Hcg Receptor

Abstract. The potency of human chorionic gonadotrophin (hCG) in competition for binding to a gonadal membrane fraction is remarkably enhanced by sialidase treatment. The present study was undertaken to investigate the specificity and characteristics of the binding of sialidase-treated hCG (asialo-hCG) in a particulate hCG-binding system from luteinized rat ovaries. The competitive potency of asialo-hCG relative to hCG was 2.5, irrespective of whether [125I]hCG or [125I]asialo-hCG was used for tracer. This was due to a 2.1 times higher equilibrium association constant for asialo-hCG, whereas the estimated number of binding sites did not differ. There was no apparent difference in the stability of hCG and asialo-hCG, or in the stability of the respective hormone-receptor complexes. The effect of variation of the incubation conditions on the binding of both tracers was similar. In accordance with the difference in the equilibrium association constant, the association velocity of asialo-hCG was more than double that of hCG. With all of the tracers used the dissociation curves were biphasic, the size of the initial fast-dissociating fraction being inversely related to the pre-incubation time. Under identical conditions, the fast-dissociating fraction was smaller for the [125I]asialo-hCG complex than for the [125I]hCG complex. The dissociation velocities of these fractions appeared to be similar. The results indicate that asialo-hCG binds to the hCG receptor in a way similar to the binding of the unmodified hormone, but with a higher affinity. The smaller size of the fast-dissociation form of the asialo-hCG-receptor complex may be related to the lower biological potency of the hormone derivative.

scholarly journals In silico decryption of serotonin–receptor binding: local non-covalent interactions and long-range conformational changes

RSC Advances ◽  
2020 ◽  
Vol 10 (62) ◽  
pp. 37995-38003
Author(s):  
Padmabati Mondal
Keyword(s):  
Long Range ◽  
Receptor Binding ◽  
Conformational Changes ◽  
In Silico ◽  
Serotonin Receptor ◽  
Receptor Complexes ◽  
Serotonin Receptor Binding ◽  
Non Covalent Interactions ◽  
The Stability ◽  
Covalent Interactions

This study is focused on identifying the main non-covalent interactions controlling the stability of serotonin–receptor complexes as well as the main conformational changes in the receptor due to serotonin–receptor binding.

scholarly journals Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1077
Author(s):  
Dasiel O. Borroto-Escuela ◽  
Luca Ferraro ◽  
Manuel Narvaez ◽  
Sergio Tanganelli ◽  
Sarah Beggiato ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Receptor Complexes ◽  
Heteroreceptor Complexes ◽  
A2a Receptor ◽  
Receptor Interactions ◽  
Relevant Role ◽  
The Central Nervous System ◽  
Adenosine A2a ◽  
The Brain

In the 1980s and 1990s, the concept was introduced that molecular integration in the Central Nervous System could develop through allosteric receptor–receptor interactions in heteroreceptor complexes presents in neurons. A number of adenosine–dopamine heteroreceptor complexes were identified that lead to the A2A-D2 heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A2A-D2 receptor–receptor interactions and their presence in the ventral striato-pallidal GABA anti-reward neurons leading to reduction of positive symptoms. Other types of adenosine A2A heteroreceptor complexes are also discussed in relation to this disease, such as A2A-D3 and A2A-D4 heteroreceptor complexes as well as higher order A2A-D2-mGluR5 and A2A-D2-Sigma1R heteroreceptor complexes. The A2A receptor protomer can likely modulate the function of the D4 receptors of relevance for understanding cognitive dysfunction in schizophrenia. A2A-D2-mGluR5 complex is of interest since upon A2A/mGluR5 coactivation they appear to synergize in producing strong inhibition of the D2 receptor protomer. For understanding the future of the schizophrenia treatment, the vulnerability of the current A2A-D2like receptor complexes will be tested in animal models of schizophrenia. A2A-D2-Simag1R complexes hold the highest promise through Sigma1R enhancement of inhibition of D2R function. In line with this work, Lara proposed a highly relevant role of adenosine for neurobiology of schizophrenia.

Sign in / Sign up

Export Citation Format

Share Document