ADP-Ribosylation Factor-Dependent Phospholipase D Activation by VPAC Receptors and a PAC<sub>1</sub>Receptor Splice Variant

McCulloch, Derek; Lutz, Eve M.; Johnson, Mark; Robertson, Derek N.; MacKenzie, Cameron A.; Holland, Pamela J.; Mitchell, Rory

doi:10.1124/mol.59.6.1523

Cited by 51 publications

(39 citation statements)

References 39 publications

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“…Using GST fusion proteins, we further investigated the interaction of ARF1 and ARF6 with the M 3 i3 domain, which is known to contain sites for interaction with heterotrimeric G proteins, arrestins, G␤␥, and the kinases GRK2 and CK1-␣ (37,(65)(66)(67). We showed previously that i3 domain splice variants of the PAC 1 receptor show marked differences in their BFA-sensitive activation of PLD but not other signaling responses (39), suggesting that M 3 i3 might be a good candidate site for ARF docking here. Specific binding of each ARF was demonstrated to the M 3 i3 GST fusion protein but not control constructs.…”

Section: Discussionmentioning

confidence: 99%

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ADP-ribosylation Factor-dependent Phospholipase D Activation by the M3 Muscarinic Receptor

Mitchell

Robertson

Holland

et al. 2003

Journal of Biological Chemistry

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G protein-coupled receptors can potentially activate phospholipase D (PLD) by a number of routes. We show here that the native M 3 muscarinic receptor in 1321N1 cells and an epitope-tagged M 3 receptor expressed in COS7 cells substantially utilize an ADP-ribosylation factor (ARF)-dependent route of PLD activation. This pathway is activated at the plasma membrane but appears to be largely independent of G q/11 , phospholipase C, Ca 2؉ , protein kinase C, tyrosine kinases, and phosphatidyl inositol 3-kinase. We report instead that it involves physical association of ARF with the M 3 receptor as demonstrated by co-immunoprecipitation and by in vitro interaction with a glutathione S-transferase fusion protein of the receptor's third intracellular loop domain. Experiments with mutant constructs of ARF1/6 and PLD1/2 indicate that the M 3 receptor displays a major ARF1-dependent route of PLD1 activation with an additional ARF6-dependent pathway to PLD1 or PLD2. Examples of other G protein-coupled receptors assessed in comparison display alternative pathways of protein kinase C-or ARF6-dependent activation of PLD2. Many G protein-coupled receptors (GPCRs)1 can activate phospholipase D (PLD), which catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline. Both phosphatidates and diacylglycerols (formed by phosphatidate hydrolysis) may act as intracellular messengers. PLD has been implicated as a key regulator of vesicular trafficking, cytoskeletal organization, exocytosis, endocytosis, and further signaling pathways (1-4). Activation of PLD can be brought about by a variety of signaling events (5-8), many of which could potentially contribute to the stimulation of PLD activity by GPCRs. These include the activation of protein kinase C (PKC), proteintyrosine kinases, phosphatidylinositol 3-kinase (PI 3-kinase), small G proteins of the ARF and Rho families, and possibly the elevation of intracellular Ca 2ϩ levels. This study addresses the mechanism of PLD activation by the M 3 muscarinic receptor expressed endogenously in 1321N1 human astrocytoma cells and heterologously in COS7 cells. The M 3 receptor is a member of the Group I, rhodopsin-related GPCR family that is expressed in the nervous system and peripheral tissues. The best established signaling pathway from the M 3 receptor is the pertussis toxin-insensitive activation of phospholipase C (PLC) via the heterotrimeric G protein G q/11 , although PLD is also strongly activated. In various cell types, PKC, protein-tyrosine kinases, ARF, and Rho have each been specifically implicated in M 3 receptor-mediated PLD activation (6, 9 -12). The data here emphasize the importance of a pathway to PLD that involves direct association between ARF and the M 3 receptor (12).ARF1 and ARF6 are representative of the main classes of cellular ARFs (Classes I and III) and have distinct subcellular distributions in many cell types. In resting cells, ARF1 is largely cytosolic or Golgi-associated, whereas ARF6 is often localized to the plasma membrane (13-17). Nevert...

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Section: Discussionmentioning

confidence: 99%

“…Agonist responses were measured usually over 30 min in the presence of 30 mM butan-1-ol. Assays were terminated, phospholipids were extracted into chloroform/methanol, and [ 3 H]PtdBut was separated by thin layer chromatography (39). Inhibitory agents and the butan-1-ol were added 30 min prior to and immediately before agonist, respectively.…”

Section: Methodsmentioning

confidence: 99%

ADP-ribosylation Factor-dependent Phospholipase D Activation by the M3 Muscarinic Receptor

Mitchell

Robertson

Holland

et al. 2003

Journal of Biological Chemistry

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“…Others G proteins that have been shown to be coupled to VPAC receptors belong to Gi/Go and Gq families (Pozo et al, 1997a;Van Rampelbergh et al, 1997;McCulloch et al, 2000;Shreeve et al, 2000;MacKenzie et al, 2001). Also, other VPAC partners different of G proteins have been reported, such as the small G-protein ADP-ribosylation factor (McCulloch et al, 2001) or receptor activity-modifying proteins (Christopoulos et al, 2003), resulting in alterations of receptor phenotype or pharmacological profile (McLatchie et al, 1998).…”

Section: B Biochemical Pharmacological and Signaling Key Features mentioning

confidence: 99%

“…Despite the conservation of alternative splicing of the Adcyap1r gene from rats to humans, there are differences regarding the role of hip and hop coupled to AC and PLC. Rat PAC 1-null , PAC 1-hop1, VPAC 1 , and VPAC 2 receptors have been reported to stimulate PLD, although less potently than AC (McCulloch et al, 2001). Interestingly, a facilitating role for the rat hop1 cassette in receptor coupling to ADP-ribosylation factor-dependent PLD activation has been reported (McCulloch et al, 2001).…”

Section: B Biochemical Pharmacological and Signaling Key Features mentioning

confidence: 99%

The Significance of Vasoactive Intestinal Peptide in Immunomodulation

Delgado

Pozo²,

Ganea³

2004

Pharmacol Rev

365

319

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“…The i3 domains of various GPCRs have been shown to provide docking sites for heterotrimeric G protein ␤␥ subunits (Wu et al, 1998) as well as arrestins (Wu et al, 1997;Gelber et al, 1999), GPCR-kinases (Wu et al, 1998), and indeed ARFs (McCulloch et al, 2001;Ronaldson et al, 2002). In a number of GPCRs, other intracellular loops and ct domains have also been implicated in interactions with heterotrimeric G proteins and arrestins (Wu et al, 1997;Oakley et al, 2001).…”

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confidence: 99%

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT_2A Receptor

Robertson

Johnson²,

Moggach³

et al. 2003

Mol Pharmacol

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The 5-hydroxytryptamine 2A receptor (5-HT 2A R) is a member of the class I family of rhodopsin-related G protein-coupled receptors. The receptor is known to activate phospholipase C via the heterotrimeric G proteins G q/11 , but we showed previously that it can also signal through the phospholipase D (PLD) pathway in an ADP-ribosylation factor (ARF)-dependent manner that seems to be independent of G q/11 (Mitchell et al., 1998). Both coimmunoprecipitation experiments and the effects of negative mutant ARF constructs on 5-HT 2A R-induced PLD activation here suggested that ARF1 may play a greater role than ARF6 in the function of this receptor. Furthermore, we demonstrated using glutathione S-transferase (GST)-fusion proteins of receptor domains that ARF1 and ARF6 bind to the third intracellular loop (i3) and the carboxy terminal tail (ct) of the 5-HT 2A R. The association of ARF1 with the ct domain of the receptor was stronger than its interaction with i3, or the interactions of ARF6 with either construct. Experiments using ARF mutants that are deficient in GTP loading, and the in vitro addition of GTP␥S suggested that GTP loading enhances ARF1 binding to the receptor. The N376PxxY motif in the transmembrane 7 domain of the receptor (rather than a N376DPxxY mutant form) was shown to be essential for ARF-dependent PLD signaling and ARF1 coimmunoprecipitation. In GST-fusion proteins of the 5-HT 2A R ct domain, mutation of Asn376 to Asp also markedly reduced ARF1-HA binding, although additional motifs in the Asn376 -Asn384 sequence and to a lesser extent elsewhere, seem also to contribute to the interaction.

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ADP-Ribosylation Factor-Dependent Phospholipase D Activation by VPAC Receptors and a PAC₁Receptor Splice Variant

Cited by 51 publications

References 39 publications

ADP-ribosylation Factor-dependent Phospholipase D Activation by the M3 Muscarinic Receptor

ADP-ribosylation Factor-dependent Phospholipase D Activation by the M3 Muscarinic Receptor

The Significance of Vasoactive Intestinal Peptide in Immunomodulation

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT_2A Receptor

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ADP-Ribosylation Factor-Dependent Phospholipase D Activation by VPAC Receptors and a PAC1Receptor Splice Variant

Cited by 51 publications

References 39 publications

ADP-ribosylation Factor-dependent Phospholipase D Activation by the M3 Muscarinic Receptor

ADP-ribosylation Factor-dependent Phospholipase D Activation by the M3 Muscarinic Receptor

The Significance of Vasoactive Intestinal Peptide in Immunomodulation

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT2A Receptor

Contact Info

Product

Resources

About

ADP-Ribosylation Factor-Dependent Phospholipase D Activation by VPAC Receptors and a PAC₁Receptor Splice Variant

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT_2A Receptor