Involvement of Receptor Cycling and Receptor Reserve in Resensitization of Muscarinic Responses in SH‐SY5Y Human Neuroblastoma Cells

Szekeres, Philip G.; Koenig, Jennifer; Edwardson, J. Michael

doi:10.1046/j.1471-4159.1998.70041694.x

Cited by 31 publications

(18 citation statements)

References 22 publications

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“…There is some evidence that the endocytic recycling compartment provides a local pool of intracellular receptors for rapid delivery to the cell surface (Szekeres et al, 1998;Lin et al, 2000;Park et al, 2004). For example, Rab11 regulates protein transport from the endocytic recycling compartment to the trans-Golgi network and the plasma membrane (Wilcke et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

The myotubularin phosphatase MTMR4 regulates sorting from early endosomes

Naughtin

Sheffield

Rahman

et al. 2010

Journal of Cell Science

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SummaryPhosphatidylinositol 3-phosphate [PtdIns(3)P] regulates endocytic trafficking and the sorting of receptors through early endosomes, including the rapid recycling of transferrin (Tfn). However, the phosphoinositide phosphatase that selectively opposes this function is unknown. The myotubularins are a family of eight catalytically active and six inactive enzymes that hydrolyse PtdIns(3)P to form PtdIns. However, the role each myotubularin family member plays in regulating endosomal PtdIns(3)P and thereby endocytic trafficking is not well established. Here, we identify the myotubularin family member MTMR4, which localizes to early endosomes and also to Rab11-and Sec15-positive recycling endosomes. In cells with MTMR4 knockdown, or following expression of the catalytically inactive MTMR4, MTMR4C407A , the number of PtdIns(3)P-decorated endosomes significantly increased. MTMR4 overexpression delayed the exit of Tfn from early endosomes and its recycling to the plasma membrane. By contrast, expression of MTMR4 C407A , which acts as a dominant-negative construct, significantly accelerated Tfn recycling. However, in MTMR4 knockdown cells Tfn recycling was unchanged, suggesting that other MTMs might also contribute to recycling. MTMR4 regulated the subcellular distribution of Rab11 and, in cells with RNAi-mediated knockdown of MTMR4, Rab11 was directed away from the pericentriolar recycling compartment. The subcellular distribution of VAMP3, a v-SNARE protein that resides in recycling endosomes and endosomederived transport vesicles, was also regulated by MTMR4. Therefore, MTMR4 localizes at the interface of early and recycling endosomes to regulate trafficking through this pathway.

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Section: Discussionmentioning

confidence: 99%

The myotubularin phosphatase MTMR4 regulates sorting from early endosomes

Naughtin

Sheffield

Rahman

et al. 2010

Journal of Cell Science

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“…Phosphorylated receptors then interact with cytoplasmic proteins termed ␤-arrestins, which interfere with receptor-G protein interaction, favoring receptor endocytosis, thus inhibiting the signal (49,50). Generally muscarinic receptor-linked PLD activity is inhibited rapidly within 2 min, but the completion of muscarinic receptor phosphorylation and internalization events are required for a longer time (51,52). Therefore, muscarinic receptor-linked PLD activity might be inhibited by another mechanism.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

Chae

Lee

et al. 2005

Journal of Biological Chemistry

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Mammalian phospholipase D (PLD) is considered a key enzyme in the transmission signals from various receptors including muscarinic receptors. PLD activation is a rapid and transient process, but a negative regulator has not been found that inhibits signal-dependent PLD activation. Here, for the first time, we report that tubulin binding to PLD 2 is an inhibition mechanism for muscarinic receptor-linked PLD 2 activation. Tubulin was identified in an immunoprecipitated PLD 2 complex from COS-7 cells by peptide mass fingerprinting. The direct interaction between PLD 2 and tubulin was found to be mediated by a specific region of PLD 2 (amino acids 476 -612). PLD 2 was potently inhibited (IC 50 <10 nM) by tubulin binding in vitro. In cells, the interaction between PLD 2 and tubulin was increased by the microtubule disrupting agent nocodazole and reduced by the microtubule stabilizing agent Taxol. Moreover, PLD 2 activity was found to be inversely correlated with the level of monomeric tubulin. In addition, we found that interaction with and the inhibition of PLD 2 by monomeric tubulin is important for the muscarinic receptor-linked PLD signaling pathway. Interaction between PLD 2 and tubulin was increased only after 1-2 min of carbachol stimulation when carbachol-stimulated PLD 2 activity was decreased. The expression of the tubulin binding region of PLD 2 blocked the later decrease in carbachol-induced PLD activity by masking tubulin binding. Taken together, these results indicate that an increase in local membrane monomeric tubulin concentration inhibits PLD 2 activity, and provides a novel mechanism for the inhibition of muscarinic receptor-induced PLD 2 activation by interaction with tubulin. Mammalian phospholipase D (PLD)1 hydrolyzes membrane phosphatidylcholine to generate phosphatidic acid and choline. PLD activity is dramatically activated in response to a variety of signals, including hormones, neurotransmitters, and growth factors (1). PLD products, phosphatidic acid itself or the hydrolyzed product diacylglycerol, have been known to act as intracellular lipid second messengers and to be involved in multiple physiological events, such as, the promotion of mitogenesis, stimulation of respiratory bursts, secretory processes, and actin cytoskeletal reorganization (2-7). Therefore, signal-dependent PLD activity must be tightly controlled in cells.Many reports have been issued about the mechanisms of receptor-mediated PLD activation. Although the mammalian PLD isozymes, PLD 1 and PLD 2 , have some different regulatory properties, in general, agonist-induced PLD is activated by various protein kinases, including protein kinase C, proteintyrosine kinase, and the MAP kinase family, in addition to small G proteins of the ARF, Rho, and Ras families (8 -13). The signal-dependent activation of PLD is rapid and transient. Although, the activation kinetics depend on the stimulus and cell type, the PLD signal is usually diminished within 10 min (14). However, the mechanisms involved in PLD signal inhibition remain unknow...

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“…Drug Treatments-For all experiments, cells were pretreated with media containing cycloheximide (20 g/ml) for 30 min to eliminate newly synthesized mAChR (16). Cycloheximide was included in all subsequent treatments.…”

Section: Methodsmentioning

confidence: 99%

Rab5-dependent Trafficking of the m4 Muscarinic Acetylcholine Receptor to the Plasma Membrane, Early Endosomes, and Multivesicular Bodies

Volpicelli

Lah

Levey

2001

Journal of Biological Chemistry

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The m4 subtype of muscarinic acetylcholine receptor regulates many physiological processes and is a novel therapeutic target for neurologic and psychiatric disorders. However, little is known about m4 regulation because of the lack of pharmacologically selective ligands. A crucial component of G protein-coupled receptor regulation is intracellular trafficking. We thus used subtype-specific antibodies and quantitative immunocytochemistry to characterize the intracellular trafficking of m4. We show that following carbachol stimulation, m4 co-localizes with transferrin, and the selective marker of early endosomes, EEA1. In addition, m4 intracellular localization depends on Rab5 activity. The dominant negative Rab5S34N inhibits m4 endocytosis initially following carbachol stimulation, and reduces the size of m4 containing vesicles. The constitutively active Rab5Q79L enhances m4 intracellular distribution, even in unstimulated cells. Rab5Q79L also produces strikingly enlarged vacuoles, which by electron microscopy contain internal vesicles, suggesting that they are multivesicular bodies. m4 localizes both to the perimeter and interior of these vacuoles. In contrast, transferrin localizes only to the vacuole perimeter, demonstrating divergence of m4 trafficking from the pathway followed by constitutively endocytosed transferrin. We thus suggest a novel model by which multivesicular bodies sort G protein-coupled receptors from a transferrin-positive recycling pathway to a nonrecycling, possibly degradative pathway.

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Involvement of Receptor Cycling and Receptor Reserve in Resensitization of Muscarinic Responses in SH‐SY5Y Human Neuroblastoma Cells

Cited by 31 publications

References 22 publications

The myotubularin phosphatase MTMR4 regulates sorting from early endosomes

The myotubularin phosphatase MTMR4 regulates sorting from early endosomes

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

Rab5-dependent Trafficking of the m4 Muscarinic Acetylcholine Receptor to the Plasma Membrane, Early Endosomes, and Multivesicular Bodies

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