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, 4 (2), 171-97

Non-neuronal Functions of the m2 Muscarinic Acetylcholine Receptor

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Non-neuronal Functions of the m2 Muscarinic Acetylcholine Receptor

Wymke Ockenga et al. Genes (Basel).

Abstract

Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinic acetylcholine receptors are ion channels, whereas the muscarinic receptors belong to the large family of G protein coupled seven transmembrane helix receptors. Beyond its function in neuronal systems, it has become evident that acetylcholine also plays an important role in non-neuronal cells such as epithelial and immune cells. Furthermore, many cell types in the periphery are capable of synthesizing acetylcholine and express at least some of the receptors. In this review, we summarize the non-neuronal functions of the muscarinic acetylcholine receptors, especially those of the M2 muscarinic receptor in epithelial cells. We will review the mechanisms of signaling by the M2 receptor but also the cellular trafficking and ARF6 mediated endocytosis of this receptor, which play an important role in the regulation of signaling events. In addition, we provide an overview of the M2 receptor in human pathological conditions such as autoimmune diseases and cancer.

Figures

Figure 1
Figure 1
Canonical signaling of muscarinic receptors. The muscarinic acetylcholine receptors (mAChRs) are coupled to trimeric G proteins that consist of α-, β- and γ-subunits. M2 and M4 receptors couple preferentially to Gi/0, whereas M1, M3 and M5 receptors mainly couple to Gq/11. Upon stimulation with acetylcholine or a related agonist, M2 and M4 receptors inhibit the activity of the adenylyl cyclase (AC), leading to a decrease in intracellular cAMP levels. In addition, both receptor subgroups can activate ion channels. M1, M3 and M5 receptors activate PKC by means of upstream PLC activation and increase in IP3 and Ca2+ levels. PKC can activate Raf kinase, leading to the activation of the MAP kinase cascade and ERK1/2. Pathways that are common for all receptor subtypes are the activation of ERK1/2 via a Src/PI3K pathway or transactivation of the EGF receptor. Transactivation of EGFR by M2 and M4 receptors occurs in a Fyn dependent mechanism, whereas M1, M3 and M5 utilize matrix metalloproteases (MMP) that release extracellular, EGF like peptides.
Figure 2
Figure 2
Structure of the M2 receptor. The M2 muscarinic acetylcholine receptor belongs to the family of G protein coupled receptors. The seven transmembrane domains (TM1-7) are connected by intracellular or extracellular loops, and the receptor exhibits four glycosylation sites at its extracellular N-terminal domain. The serine residues 96 and 176 in the first and second extracellular loop are connected to each other by a disulfide bond. Except for the third intracellular (i3) loop, other loops are relatively small. The i3 loop consists of 181 amino acids and has no specific secondary structure. The C-terminal domain and the i3 loop can be phosphorylated at several residues.
Figure 3
Figure 3
Agonist stimulated internalization of the M2 receptor. The M2 receptor is internalized by a clathrin-independent, ARF6-dependent pathway. Upon agonist stimulation, the M2 receptor is phosphorylated on serine/threonine residues by GRK, which facilitates the binding of β-arrestins and receptor desensitization. In addition, the β-arrestin activates ARF6, resulting in M2 receptor internalization in the early endosome. A phosphatase dephosphorylates the M2 receptor, causing β-arrestin dissociation from the receptor. The small G protein Rab22 has been implicated in the recycling of the M2 receptor. However, recycling appears to be a minor route for the M2 receptor which is mainly targeted to lysosomes and degraded.

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