Allosteric properties of G protein-coupled receptors — The example of muscarinic acetylcholine receptors

2000 ◽  
Vol 10 ◽  
pp. 213-214
Author(s):  
N.J.M. Birdsall ◽  
S. Lazareno
Keyword(s):  
G Protein ◽  
Acetylcholine Receptors ◽  
G Protein Coupled Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Muscarinic Acetylcholine ◽  
G Protein Coupled ◽  
Allosteric Properties

Steroids as the novel class of high-affinity allosteric modulators of muscarinic receptors

2021 ◽  
Author(s):  
Eva Dolejší ◽  
Eszter Szánti-Pintér ◽  
Nikolai Chetverikov ◽  
Dominik Nelic ◽  
Alena Randáková ◽  
...  
Keyword(s):  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Allosteric Modulators ◽  
The Novel ◽  
Stress Control ◽  
Structure Activity ◽  
G Protein Coupled

Abstract The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone, and some neurosteroids bound to muscarinic receptors with an affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol-binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.

scholarly journals Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Anja Floeser ◽  
Katharina Becker ◽  
Evi Kostenis ◽  
Gabriele König ◽  
Cornelius Krasel ◽  
...  
Keyword(s):  
G Protein ◽  
Acetylcholine Receptor ◽  
Rank Order ◽  
Muscarinic Acetylcholine Receptor ◽  
G Protein Coupled Receptors ◽  
Effector Proteins ◽  
Muscarinic Acetylcholine ◽  
Extracellular Signals ◽  
G Protein Coupled ◽  
Different Levels

G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses – termed bias – potentially by eliciting different levels of recruitment of effector proteins. As activation and recruitment of effector proteins might influence each other, thorough analysis of bias is difficult. Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based assays. In order to avoid interference between these interactions, we studied GRK2 binding in the presence of inhibitors of Gi and Gq proteins and analyzed arrestin3 binding to prestimulated M3 receptors to avoid differences in receptor phosphorylation influencing arrestin recruitment. We measured substantial differences in the agonist efficacies to induce M3R-arrestin3 versus M3R-GRK2 interaction. However, the rank order of the agonists for G protein- and GRK2-M3R interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations, whereas requirements for arrestin3 binding to M3R are distinct.

scholarly journals Regulation of extracellular-signal regulated kinase and c-Jun N-terminal kinase by G-protein-linked muscarinic acetylcholine receptors

1999 ◽  
Vol 338 (3) ◽  
pp. 619-628 ◽  
Author(s):  
Paul G. WYLIE ◽  
R. A. John CHALLISS ◽  
Jonathan L. BLANK
Keyword(s):  
G Protein ◽  
Acetylcholine Receptors ◽  
Chinese Hamster ◽  
Muscarinic Acetylcholine Receptors ◽  
Significant Component ◽  
Inflammatory Reactions ◽  
Erk Activation ◽  
Muscarinic Acetylcholine ◽  
Extracellular Signal ◽  
Jnk Activation

Extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs, or stress-activated protein kinases) are activated by diverse extracellular signals and mediate a variety of cellular responses, including mitogenesis, differentiation, hypertrophy, inflammatory reactions and apoptosis. We have examined the involvement of Ca2+ and protein kinase C (PKC) in ERK and JNK activation by the human G-protein-coupled m2 and m3 muscarinic acetylcholine receptors (mAChR) expressed in Chinese hamster ovary (CHO) cells. We show that the Ca2+-mobilizing m3 AChR is efficiently coupled to JNK and ERK activation, whereas the m2 AChR activates ERK but not JNK. Activation of JNK in CHO-m3 cells by the agonist methacholine (MCh) was delayed in onset and more sustained relative to that of ERK in either CHO-m2 or CHO-m3 cells. The EC50 values for MCh-induced ERK activation in both cell types were essentially identical and similar to that for JNK activation in CHO-m3 cells, suggesting little amplification of the response. Agonist-stimulated Ins(1,4,5)P3 accumulation in CHO-m3 cells was insensitive to pertussis toxin (PTX), consistent with a Gq/phosphoinositide-specific phospholipase C-β mediated pathway, whereas a significant component of ERK and JNK activation in CHO-m3 cells was PTX-sensitive, indicating Gi/o involvement. Using manipulations that prevent receptor-mediated extracellular Ca2+ influx and intracellular Ca2+-store release, we also show that ERK activation by m2 and m3 receptors is Ca2+-independent. In contrast, a significant component (> 50%) of JNK activation mediated by the m3 AChR was dependent on Ca2+, mainly derived from extracellular influx. PKC inhibition and down-regulation studies suggested that JNK activation was negatively regulated by PKC. Conversely, ERK activation by both m2 and m3 AChRs required PKC, suggesting a novel mechanism for PKC activation by PTX-sensitive m2 AChRs. In summary, mAChRs activate JNK and ERK via divergent mechanisms involving either Ca2+ or PKC respectively.

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