A Novel Mechanism for Coupling of m4 Muscarinic Acetylcholine Receptors to Calmodulin-Sensitive Adenylyl Cyclases: Crossover from G Protein-Coupled Inhibition to Stimulation

Biochemistry ◽  
1994 ◽  
Vol 33 (4) ◽  
pp. 943-951 ◽  
Author(s):  
Andrew H. Dittman ◽  
Jed P. Weber ◽  
Thomas R. Hinds ◽  
Eui Ju Choi ◽  
Jacques C. Migeon ◽  
...  
Keyword(s):  
G Protein ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Adenylyl Cyclases ◽  
Muscarinic Acetylcholine ◽  
G Protein Coupled

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.

scholarly journals Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes

Science ◽  
2019 ◽  
Vol 364 (6440) ◽  
pp. 552-557 ◽  
Author(s):  
Shoji Maeda ◽  
Qianhui Qu ◽  
Michael J. Robertson ◽  
Georgios Skiniotis ◽  
Brian K. Kobilka
Keyword(s):  
G Protein ◽  
Acetylcholine Receptors ◽  
Protein Complexes ◽  
Transmembrane Helix ◽  
Muscarinic Acetylcholine Receptor ◽  
Muscarinic Acetylcholine Receptors ◽  
Receptor Subtypes ◽  
Muscarinic Acetylcholine ◽  
High Degree ◽  
Distinct Features

Muscarinic acetylcholine receptors are G protein–coupled receptors that respond to acetylcholine and play important signaling roles in the nervous system. There are five muscarinic receptor subtypes (M1R to M5R), which, despite sharing a high degree of sequence identity in the transmembrane region, couple to different heterotrimeric GTP-binding proteins (G proteins) to transmit signals. M1R, M3R, and M5R couple to the Gq/11 family, whereas M2R and M4R couple to the Gi/o family. Here, we present and compare the cryo–electron microscopy structures of M1R in complex with G11 and M2R in complex with GoA. The M1R-G11 complex exhibits distinct features, including an extended transmembrane helix 5 and carboxyl-terminal receptor tail that interacts with G protein. Detailed analysis of these structures provides a framework for understanding the molecular determinants of G-protein coupling selectivity.

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