Kinetics of M1 muscarinic receptor and G protein signaling to phospholipase C in living cells

Falkenburger, Björn H.; Jensen, Jill B.; Hille, Bertil

doi:10.1085/jgp.200910344

Cited by 101 publications

(138 citation statements)

References 52 publications

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“…We acknowledge that overexpression of M 1 receptors might result in much greater numbers of receptors expressed in the membrane of the neurons, resulting in greater or faster turn-on of G␣ q/11 and PLC for a given concentration of agonist. Quantification of the increase over endogenous levels of membrane proteins by their expression suggests that this factor might be as large as 100-fold, although most expressed proteins would probably not be in the plasma membrane (90). However, that same paper concludes that the steps of agonist binding to receptors and receptor activation of G q/11 and PLC are much faster than PLC-mediated hydrolysis of PIP 2 , and thus it is the number of PLC molecules that largely determines the speed and amount of IP 3 production, at least at the supramaximal agonist concentrations used here.…”

Section: Discussionmentioning

confidence: 99%

Combined Phosphoinositide and Ca2+ Signals Mediating Receptor Specificity toward Neuronal Ca2+ Channels

Zaika

Zhang

Shapiro

2011

Journal of Biological Chemistry

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Phosphoinositides comprise a diverse array of plasma membrane signaling molecules with temporal effects ranging from 1 ms to the lifetime of the organism. Most intensively studied are the polyphosphorylated phosphatidylinositols (PIs). 2 The species phosphorylated at the 4Ј-and 5Ј-positions of the inositol ring by PI 4-kinase and PI 4-phosphate (PI(4)P) 5-kinase, called PI 4,5-bisphosphate (PIP 2 ), have been implicated as a critical player in myriad cellular activities. These include cytoskeletal remodeling, vesicular/protein trafficking among intracellular membranes, transcriptional control, and regulation of ion channels and transporters. Regarding the latter role, a large and widening array of such membrane transport proteins have been shown to be regulated by plasma membrane PIP 2 , presumably due to direct binding (1, 2). The action is thought to arise from either PIP 2 depletion by stimulation of phospholipase C (PLC)-coupled receptors or from alterations in the affinity of PIP 2 for the channels caused by generation of other signaling molecules (3). Using sympathetic neurons of the superior cervical ganglion (SCG) as a model, we have focused on PIP 2 -mediated regulation of voltage-gated "M-type" (KCNQ) K ϩ and "N-type" Ca 2ϩ currents. The former is so named for its depression by muscarinic stimulation, whose mechanism has been established as being due to depletion of PIP 2 (4 -9). The latter is also PIP 2 -sensitive (10 -12) as well as sensitive to arachidonic acid (13), and stimulation of PLC-linked muscarinic receptors likewise depresses I Ca in the same neurons (10,14). However, stimulation of other PLC-linked receptors (bradykinin B 2 and purinergic P2Y) in those neurons does not deplete PIP 2 and displays a pattern of M-current depression via intracellular Ca 2ϩ (Ca 2ϩ i ) signals (15, 16), acting on KCNQ channels via calmodulin (CaM) (17, 18), and little action on the N-type I Ca (10, 14) (although many Ca V channels are modulated by CaM, the N-type channels are probably insensitive to [Ca 2ϩ ] i rises in the range (Ͻ2 M) reachable by release from stores).This receptor specificity parallels stark receptor specificity in the induction of IP 3 -mediated [Ca 2ϩ

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Section: Discussionmentioning

confidence: 99%

Combined Phosphoinositide and Ca2+ Signals Mediating Receptor Specificity toward Neuronal Ca2+ Channels

Zaika

Zhang

Shapiro

2011

Journal of Biological Chemistry

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“…87). Recent estimates of PtdIns(4,5)P 2 density in the plasma membrane (PM) ranged between 5,000 -20,000 molecules/m 2 (421). The other PPIs contribute even smaller amounts, PtdIns(3,4,5)P 3 being about 2-5% of PtdIns(4,5)P 2 and PtdIns3P about 20 -30% of PtdIns4P.…”

Section: Based On Long-term [mentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,393

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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“…We studied the M 1 muscarinic acetylcholine receptor (M 1 R), which couples to both G q -and arrestin-dependent pathways, including ERK activation (19)(20)(21)(22), and found strong evidence for two binding modes of arrestin to receptors that led to contrasting downstream signals. The M 1 R is a receptor for which desensitization and internalization are relatively weaker than for, for example, the β 2 -adrenergic receptor.…”

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confidence: 99%

Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding

Jung

Kushmerick

Seo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Binding of agonists to G-protein-coupled receptors (GPCRs) activates heterotrimeric G proteins and downstream signaling. Agonistbound GPCRs are then phosphorylated by protein kinases and bound by arrestin to trigger desensitization and endocytosis. Arrestin plays another important signaling function. It recruits and regulates activity of an extracellular signal-regulated kinase (ERK) cascade. However, molecular details and timing of ERK activation remain fundamental unanswered questions that limit understanding of how arrestin-dependent GPCR signaling controls cell functions.Here we validate and model a system that tracks the dynamics of interactions of arrestin with receptors and of ERK activation using optical reporters. Our intermolecular FRET measurements in living cells are consistent with β-arrestin binding to M 1 muscarinic acetylcholine receptors (M 1 Rs) in two different binding modes, transient and stable. The stable mode persists for minutes after agonist removal. The choice of mode is governed by phosphorylation on key residues in the third intracellular loop of the receptor. We detect a similar intramolecular conformational change in arrestin in either binding mode. It develops within seconds of arrestin binding to the M 1 receptor, and it reverses within seconds of arrestin unbinding from the transient binding mode. Furthermore, we observed that, when stably bound to phosphorylated M 1 R, β-arrestin scaffolds and activates MEK-dependent ERK. In contrast, when transiently bound, β-arrestin reduces ERK activity via recruitment of a protein phosphatase. All this ERK signaling develops at the plasma membrane. In this scaffolding hypothesis, a shifting balance between the two arrestin binding modes determines the degree of ERK activation at the membrane.arrestin | GPCR | ERK | muscarinic receptor | receptor kinase A rrestin plays a fundamental role in the negative regulation of G-protein-coupled receptors (GPCRs) signaling because its binding to GPCRs hinders G-protein association with the receptors (1-5). Arrestin further recruits adaptor proteins and clathrin for the internalization and desensitization of the receptor (6). Additional functions have been suggested, with β-arrestin producing its own signaling through interactions with other effectors (7-9). For example, β-arrestin has binding sites for cRaf (MAPK kinase kinase), MEK (MAPK kinase), and ERK (MAPK) that mediate a signaling cascade for cell proliferation, cell migration, and actin dynamics after GPCR activation (10-13). Conventionally, MEK-dependent ERK signaling is described as involving GPCR-arrestin complexes on intracellular compartments such as endosomal vesicles (10, 14-16). However, whether similar complexes at the plasma membrane might trigger ERK signaling remains unknown. Electron microscope images of arrestin-receptor complexes together with modeling suggest that β-arrestin binds in two different modes, called transient binding and stable binding, to chimeric β 2 adrenergic receptors (β 2 -AR) containing the C terminus of vasopre...

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Kinetics of M1 muscarinic receptor and G protein signaling to phospholipase C in living cells

Cited by 101 publications

References 52 publications

Combined Phosphoinositide and Ca2+ Signals Mediating Receptor Specificity toward Neuronal Ca2+ Channels

Combined Phosphoinositide and Ca2+ Signals Mediating Receptor Specificity toward Neuronal Ca2+ Channels

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding

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