Muscarinic M4 Receptor Recycling Requires a Motif in the Third Intracellular Loop

@article{Hashimoto2008MuscarinicMR,
  title={Muscarinic M4 Receptor Recycling Requires a Motif in the Third Intracellular Loop},
  author={Yuichi Hashimoto and Kanoko Morisawa and Hiroyuki Saito and Eri Jojima and Norihiro Yoshida and Tatsuya Haga},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2008},
  volume={325},
  pages={947 - 953}
}
The present study was performed to identify sequence(s) in the third intracellular loop (i3) of the muscarinic acetylcholine receptor M4 subtype (M4 receptor) involved in its internalization and recycling. In transiently transfected human embryonic kidney 293-tsA201 cells, 40 to 50% of cell-surface M4 receptors are internalized in an agonist-dependent manner, and approximately 65% of internalized receptors are recycled back to the cell surface after removal of the agonist. We examined the… 
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Role of the third intracellular loop in the subtype-specific internalization and recycling of muscarinic M2 and M4 receptors.

Internalized M2/M4-i3/M2 receptors as well as internalized M4 receptors were shown to be recycled back to the cell surface after removal of agonists, whereas no recycling was observed for M4/M 2-i 3/M 4 receptors aswell as M2 receptors, indicating that the i3 loops of M2 and M4 receptor take a major role in their agonist-dependent internalization and recycling.

Unraveling a molecular determinant for clathrin-independent internalization of the M2 muscarinic acetylcholine receptor

The data indicate that endocytosis and postendocytic sorting of GPCRs that undergo CIE could be sequence-dependent, and identified that the sequence 374KKKPPPS380 servers as a sorting signal for the clathrin-independent internalization of M2 mAChR.

Modulation of M4 muscarinic acetylcholine receptors by interacting proteins

In striatal neurons where M4Rs are most abundantly expressed, M4RIPs dynamically control M4R activity to maintain a proper cholinergic tone in these neurons, which is critical for maintaining the acetylcholine-dopamine balance in the basal ganglia.

Modulation of M4 muscarinic acetylcholine receptors by interacting proteins

In striatal neurons where M4Rs are most abundantly expressed, M4RIPs dynamically control M4R activity to maintain a proper cholinergic tone in these neurons, which is critical for maintaining the acetylcholine-dopamine balance in the basal ganglia.

Molecular properties of muscarinic acetylcholine receptors

  • T. Haga
  • Biology, Chemistry
    Proceedings of the Japan Academy. Series B, Physical and biological sciences
  • 2013
The molecular properties of muscarinic receptors are summarized with reference to the historical background and bias to studies performed in the laboratories, with particular attention to the crystal structures of M2 and M3 receptors.

A Rab10–ACAP1–Arf6 GTPases cascade modulates M4 muscarinic acetylcholine receptor trafficking and signaling

The role of the small GTPase Rab10 as a negative regulator for the post-activation trafficking of M4 mAChR and the underlying mechanism are revealed and a model that Rab10 binds to the M4 like a molecular brake and controls the receptor’s transport through endosomes, thus modulating the signaling, is suggested.

Structure-function studies of M4 muscarinic acetylcholine receptor allosteric modulation

Alanine scanning mutagenesis was utilised in conjunction with radioligand assays to determine the role of specific amino acid residues on affinity or binding cooperativity, and M4 mAChR-mediated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, as a measure of efficacy or functional modulation by LY2033298.

Signaling Diversity Mediated by Muscarinic Acetylcholine Receptor Subtypes and Evidence for Functional Selectivity

Why there is currently little available evidence for functional selectivity at mACh receptors is discussed and whether this situation will change as more subtype-selective ligands, and ligands that act on mA Ch receptors at sites other than the acetylcholine binding site are developed and explored is speculated.

Regulation and trafficking of muscarinic acetylcholine receptors

23 Muscarinic Acetylcholine Receptor

An overview of the historical background and current studies of muscarinic receptors is presented focusing on studies carried out in the laboratory.

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