The C-terminal tail of the M3-muscarinic receptor possesses anti-apoptotic properties

被引:54
作者
Budd, DC
McDonald, J
Emsley, N
Cain, K
Tobin, AB
机构
[1] Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 9HN, Leics, England
[2] Univ Leicester, MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England
关键词
D O I
10.1074/jbc.M211670200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
This study investigates the mechanisms by which the muscarinic receptor gene family can protect against apoptosis. Chinese hamster ovary cells transfected with human muscarinic receptor subtypes underwent apoptotic cell death following treatment with the DNA-damaging agent etoposide. Apoptosis was significantly reduced following muscarinic receptor stimulation of cells that were transfected with receptor subtypes that couple to the G(q/11)/phospholipase C pathway, namely M-1, M-3, and M-5. No protection was detected in cells transfected with the G(i)-coupled M-2 and M-4 receptors. Further analysis of the G(q/11)-coupled M-3 receptor revealed that truncation of the carboxyl-tail (Delta565-M-3 mutant) removed the ability of the receptor to protect against etoposide-induced cell death. This mutation did not affect the ability of the receptor to signal through the phospholipase C pathway. Furthermore, activation of the Delta565-M-3 receptor resulted in robust activation of the extracellular-regulated kinase (ERK) and c-Jun kinase (JNK). The Delta565-M-3 receptor mutant also underwent agonist-driven phosphorylation in a similar manner to the wild-type receptor indicating that the anti-apoptotic effect of the M3 receptor is independent of receptor phosphorylation. Consistent with this was the fact that two M-3-muscarinic receptor mutants deficient in agonist-induced receptor phosphorylation were capable of producing a full anti-apoptotic response. We conclude that the anti-apoptotic response of the muscarinic receptor family was confined to the G(q/11)-coupled members of this family. The direct involvement of G(q/11)/phospholipase C signaling and the ERK-1/2 and JNK pathways together with receptor phosphorylation in the anti-apoptotic response were eliminated. Mutation of a poly-basic region within the short C-terminal tail of the M-3-muscarinic receptor inhibited the ability of the receptor to induce an anti-apoptotic response. We conclude that the conserved poly-basic region in the C-terminal tail of the M-1, M-3, and M-5 receptors contributes to the ability of these receptors to mediate protection against apoptotic cell death.
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页码:19565 / 19573
页数:9
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