Differential Regulation of Muscarinic Acetylcholine Receptor-sensitive Polyphosphoinositide Pools and Consequences for Signaling in Human Neuroblastoma Cells

Willars, Gary B.; Nahorski, Stefan R.; Challiss, R. A. John

doi:10.1074/jbc.273.9.5037

Cited by 163 publications

(200 citation statements)

References 43 publications

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“…Furthermore, incubation of these cells with 10 M wortmannin for 10 min markedly attenuates transient peaks of both InsP 3 accumulation and intracellular Ca 2ϩ elevation evoked by subsequent stimulation of M 3 -muscarinic receptor. These data support the view that micromolar concentrations of wortmannin not only inhibits the replenishment of PtdIns(4,5)P 2 following PLC-coupled receptor-mediated depletion (30,41,42) but also substantially reduces membrane PtdIns(4,5)P 2 pool even under basal conditions through the inhibition of wortmannin-sensitive isoform of PtdIns 4-kinase (30). The present finding that extracellular ATP is still effective at potentiating I Ks in wortmannin-treated atrial myocytes (Fig.…”

Section: Discussionsupporting

confidence: 80%

“…The present result that the stimulatory action of 50 M wortmannin on I Ks is completely abolished by the concomitant presence of exogenous PtdIns(4,5)P 2 ( Fig. 2C and 3 basal conditions (30). Furthermore, incubation of these cells with 10 M wortmannin for 10 min markedly attenuates transient peaks of both InsP 3 accumulation and intracellular Ca 2ϩ elevation evoked by subsequent stimulation of M 3 -muscarinic receptor.…”

Section: Discussionmentioning

confidence: 51%

“…We also checked whether extracellular ATP can further enhance I Ks in wortmannin-treated myocytes in which membrane PtdIns(4,5)P 2 level is expected to be substantially reduced (30). As demonstrated in Fig.…”

Section: Involvement Of Ptdins(45)p 2 Depletion In Extracellular Atpmentioning

confidence: 97%

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Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

Ding

Toyoda

Matsuura

2004

Journal of Biological Chemistry

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Regulation of the slowly activating component of delayed rectifier K ؉ current (I Ks ) by membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PtdIns-(4,5)P 2 ) was examined in guinea pig atrial myocytes using the whole-cell patch clamp method. I Ks was elicited by depolarizing voltage steps given from a holding potential of ؊50 mV, and the effect of various test reagents on I Ks was assessed by measuring the amplitude of tail current elicited upon return to the holding potential following a 2-s depolarization to ؉30 mV. Intracellular application of 50 M wortmannin through a recording pipette evoked a progressive increase in I Ks over a 10 -15-min period to 208.5 ؎ 14.6% (n ‫؍‬ 9) of initial magnitude obtained shortly after rupture of the patch membrane. Intracellular application of anti-PtdIns(4,5)P 2 monoclonal antibody also increased the amplitude of I Ks to 198.4 ؎ 19.9% (n ‫؍‬ 5). In contrast, intracellular loading with exogenous PtdIns(4,5)P 2 at 10 and 100 M produced a marked decrease in the amplitude of I Ks to 54.3 ؎ 3.8% (n ‫؍‬ 5) and 44.8 ؎ 8.2% (n ‫؍‬ 5), respectively. Intracellular application of neomycin (50 M) or aluminum (50 M) evoked an increase in the amplitude of I Ks to 161.0 ؎ 13.5% (n ‫؍‬ 4) and 150.0 ؎ 8.2% (n ‫؍‬ 4), respectively. These results strongly suggest that I Ks channel is inhibited by endogenous membrane PtdIns(4,5)P 2 through the electrostatic interaction with the negatively charged head group on PtdIns(4,5)P 2 . Potentiation of I Ks by P2Y receptor stimulation with 50 M ATP was almost totally abolished when PtdIns(4,5)P 2 was included in the pipette solution, suggesting that depletion of membrane PtdIns(4,5)P 2 is involved in the potentiation of I Ks by P2Y receptor stimulation. Thus, membrane PtdIns(4,5)P 2 may act as an important physiological regulator of I Ks in guinea pig atrial myocytes.The delayed rectifier K ϩ current (I K ) 1 is activated by membrane depolarization and thereby provides an outward current, which is essential for initiating phase 3 repolarization of the action potential in cardiac muscle. Two kinetically and pharmacologically distinct components of I K , I Kr (rapid) and I Ks (slow), have been identified in cardiac myocytes from various mammalian species (1, 2) including humans (3). The KCNQ1 gene encodes the pore-forming ␣ subunit, K V LQT1, that assembles with an accessory ␤ subunit minK (I sK ) protein (encoded by KCNE1 gene) to produce the I Ks channel (4, 5), whereas the HERG (human ether-á -go-go-related gene) product forms the pore-forming subunit of the I Kr channel (6, 7). Mutations in any of these genes have been linked to long QT syndrome, an inherited cardiac arrhythmia characterized by abnormal ventricular repolarization and a high risk for sudden cardiac death (8).Previous studies have demonstrated that both I Ks and I Kr represent relevant targets for the actions of autonomic neurotransmitters, hormones, intracellular messengers, and exogenous drugs. I Ks is modulated by protein kinase A, protein kinase C (PKC), and intracellular ...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 51%

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Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

Ding

Toyoda

Matsuura

2004

Journal of Biological Chemistry

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“…Activators of these GPCRs can dramatically deplete membrane PtdIns(4,5)P 2 levels within seconds of agonist addition [47], raise the intracellular concentration of Ca 2þ many-fold, and recruit and activate several PKC isoenzymes through increases in the levels of diacylglycerol and/or Ca 2þ Membrane association of the different GRKs is regulated by multiple factors (e.g. covalent lipidation and Gbg binding), and it is therefore possible that local or global PtdIns(4,5)P 2 depletion might differentially affect the anchoring of the GRK2 and GRK3 proteins at the plasma membrane compared with members of the GRK4 subfamily [10].…”

Section: Does the Regulation Of Non-visual Grks Provide Clues To Theimentioning

confidence: 99%

Non-visual GRKs: are we seeing the whole picture?

Willets

Challiss

Nahorski

2003

Trends in Pharmacological Sciences

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G-protein-coupled receptor kinases (GRKs) comprise a family of seven mammalian serine/threonine protein kinases that phosphorylate and regulate agonist-occupied or constitutively active G-protein-coupled receptors (GPCRs). Studies of the details and consequences of these mechanisms have focused heavily on the original b-adrenoceptor kinase (b-ARK) family (GRK2 and GRK3) and, in particular, on phosphorylation-dependent recruitment of adaptor proteins such as the b-arrestins. However, recent work has indicated roles for the other, non-visual GRKs (GRK4, GRK5 and GRK6) and has revealed potential phosphorylation-independent regulation of GPCRs by GRK2 and GRK3. In this article, we review this newer information and attempt to put it into context with GRKs as physiological regulators that could be appropriate targets for future pharmacological intervention.G-protein-coupled receptors (GPCRs) constitute a very large family of heptahelical, integral membrane proteins that mediate a wide variety of physiological processes ranging from the transmission of light and odorant signals to the mediation of neurotransmission and hormonal actions [1,2]. GPCRs represent a major target for therapeutic agents, and the continuing identification of orphan GPCRs offers opportunity for future pharmacological and therapeutic development [3].Most GPCRs display a rapid loss of responsiveness in the continuing (or recurring) presence of an agonist or stimulus, and there is now substantial evidence that this process of desensitization, at least in part, is a consequence of ligand-induced phosphorylation of serine and threonine residues located within the C-terminal domain and/or the third intracellular loop of GPCRs. Two families of protein kinases appear to be predominantly involved: the G-protein-coupled receptor kinases (GRKs), which phosphorylate agonist-occupied GPCRs to mediate homologous receptor phosphorylation, and the second messengeractivated kinases, such as cAMP-dependent kinase (PKA) and protein kinase C (PKC), which can phosphorylate both ligand-bound and other inactive GPCRs in a heterologous manner [4,5]. Phosphorylation by GRKs enhances receptor affinity for non-visual b-arrestins 1 and 2 (arrestin2 and arrestin3), which not only sterically suppresses further interaction between the receptor and G proteins, but also initiates clathrin-mediated endocytosis of phosphorylated receptors and can promote the activation of additional signalling pathways by acting as agonist-regulated adaptor scaffolds [6].Other protein kinases have also been implicated in GPCR regulation. For example, evidence has accumulated that casein kinase 1a might bring about agonistmediated phosphorylation of acetylcholine muscarinic M 3 receptors and light-activated rhodopsin [7]. Casein kinase 1a-mediated phosphorylation does not appear to be associated with reduced responsiveness of the M 3 receptor but probably contributes to the activation of extracellular signal-regulated kinases 1 and 2 (ERK1,2) by this receptor [8,9].Although research in this area h...

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“…PI 4-kinase IIIβ is said to be localized to the Golgi and nucleus and contributes to the biosynthesis of Golgi PI(4)P through its association with Arf1 and neuronal calcium sensor 1 (19-21). Inhibition of PI 4-kinase IIIα and -β with micromolar concentrations of wortmannin prevents the replenishment of PM PI(4,5)P 2 following PLC activation (10,22,23). Type IIα and IIβ PI4Ks are membrane-bound proteins due to the palmitoylation of a conserved stretch of cysteines in their catalytic domains (24).…”

mentioning

confidence: 99%

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P ₂ and maintenance of KCNQ2/3 ion channel current

Dickson

Jensen

Hille

2014

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

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Plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] regulates the activity of many ion channels and other membrane-associated proteins. To determine precursor sources of the PM PI(4,5)P 2 pool in tsA-201 cells, we monitored KCNQ2/3 channel currents and translocation of PH PLCδ1 domains as real-time indicators of PM PI(4,5)P 2 , and translocation of PH OSH2×2 , and PH OSH1 domains as indicators of PM and Golgi phosphatidylinositol 4-phosphate [PI(4)P], respectively. We selectively depleted PI(4)P pools at the PM, Golgi, or both using the rapamycin-recruitable lipid 4-phosphatases. Depleting PI(4)P at the PM with a recruitable 4-phosphatase (Sac1) results in a decrease of PI(4,5)P 2 measured by electrical or optical indicators. Depleting PI(4)P at the Golgi with the 4-phosphatase or disrupting membrane-transporting motors induces a decline in PM PI(4,5)P 2 . Depleting PI(4)P simultaneously at both the Golgi and the PM induces a larger decrease of PI(4,5)P 2 . The decline of PI(4,5)P 2 following 4-phosphatase recruitment takes 1-2 min. Recruiting the endoplasmic reticulum (ER) toward the Golgi membranes mimics the effects of depleting PI(4)P at the Golgi, apparently due to the trans actions of endogenous ER Sac1. Thus, maintenance of the PM pool of PI(4,5)P 2 appears to depend on precursor pools of PI(4)P both in the PM and in the Golgi. The decrease in PM PI(4,5)P 2 when Sac1 is recruited to the Golgi suggests that the Golgi contribution is ongoing and that PI (4,5)P 2 production may be coupled to important cell biological processes such as membrane trafficking or lipid transfer activity.phosphoinositides | wortmannin | pleckstrin homology domain T his paper concerns the dynamics of cellular pools of phosphoinositides, a family of phospholipids located on the cytoplasmic leaflet of cellular membranes, that maintain cell structure, cell motility, membrane identity, and membrane trafficking; they also play key roles in signal transduction (1). Phosphatidylinositol (PI) can be phosphorylated at three positions to generate seven additional species. The subcellular localization of each phosphoinositide is tightly governed by the concurrent presence of lipid kinases and lipid phosphatases (2, 3), giving each membrane within the cell a unique and dynamic phosphoinositide signature (4). Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] is localized to the inner leaflet of the plasma membrane (PM) and is the major substrate of phospholipase C (PLC). As a consequence, PI(4,5)P 2 levels are dynamically regulated by G q -coupled receptors activating PLC. The activity of lipid kinases and phosphatases also can be modulated by signaling; for example, a PI 4-kinase, when associated with neuronal calcium sensor-1, is accelerated in response to elevated calcium that occurs with PI(4,5)P 2 cleavage (5). In addition, transient apposition between organelles can alter phosphoinositide levels by presenting membrane-bound phosphatases in trans. For example, the endoplasmic reticulum (ER) can make contacts with the...

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Differential Regulation of Muscarinic Acetylcholine Receptor-sensitive Polyphosphoinositide Pools and Consequences for Signaling in Human Neuroblastoma Cells

Cited by 163 publications

References 43 publications

Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

Non-visual GRKs: are we seeing the whole picture?

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P ₂ and maintenance of KCNQ2/3 ion channel current

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Differential Regulation of Muscarinic Acetylcholine Receptor-sensitive Polyphosphoinositide Pools and Consequences for Signaling in Human Neuroblastoma Cells

Cited by 163 publications

References 43 publications

Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate

Non-visual GRKs: are we seeing the whole picture?

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P 2 and maintenance of KCNQ2/3 ion channel current

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About

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P ₂ and maintenance of KCNQ2/3 ion channel current