Protein Kinase A-mediated Phosphorylation of Serine 357 of the Mouse Prostacyclin Receptor Regulates Its Coupling to Gs-, to Gi-, and to Gq-coupled Effector Signaling

Lawler, Orlaith A.; Miggin, Sinéad M.; Kinsella, B. Thérèse

doi:10.1074/jbc.m104434200

Cited by 113 publications

(69 citation statements)

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“…Deletion-and Site-directed Mutagenesis of Human Prostacyclin Receptor-The plasmids pBluescript-hIP and pHM-hIP have been previously described (20,26 , TGC to TAG). Deletion mutagenesis of hIP was performed using pBluescript-hIP as a PCR template, employing Expand High Fidelity Taq DNA polymerase and the oligonucleotide primers: 5Ј-G AGA AGC TTG ATG GCG GAT TCG TGC AGG-3Ј (sense primer; nucleotides ϩ1 to ϩ18 of hIP sequences are underlined) and 5Ј-ATA TGA ATT CTA GAC CCA GAG CTT GAG TCG C-3Ј (antisense primer; the sequences complimentary to nucleotides ϩ 902 to ϩ 920 of hIP are underlined, and the mutator in-frame stop codon is in bold type).…”

Section: Methodsmentioning

confidence: 99%

“…FURA2/AM was purchased from Calbiochem. [ 3 H] i P 3 (20 -40 Ci/mmol) and [ 3 H]cAMP (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) Ci/mmol) were purchased from American Radiolabeled Chemicals Inc. [ 3 H]Iloprost (15.3Ci/mmol) was purchased from Amersham Biosciences. [9,10-3 H]Palmitic acid (60 Ci/mmol) was obtained from PerkinElmer Life Sciences.…”

Section: Methodsmentioning

confidence: 99%

“…The prostacyclin receptor, also termed the IP (16), signals primarily through activation of adenylyl cyclase via G s (17,18) but may also couple to other G protein-effector systems including G q -dependent activation of phospholipase (PL) C and mobilization of intracellular calcium (18,19). Recently, it was established that in addition to G s , the mouse IP also couples to inhibition of adenylyl cyclase via G i and to G q /PLC activation through a switching mechanism involving its initial coupling to G s /adenylyl cyclase activation and subsequent cAMP-dependent protein kinase A phosphorylation of the mouse IP at Ser 357 within its C-tail region (20). Additionally, IPs are widely reported to undergo rapid agonist-induced desensitization, internalization, and down-regulation in human platelets and in other cell types (21)(22)(23)(24).…”

Section: Superfamily (1 2 4 5)mentioning

confidence: 99%

“…Conversion of Cys 309 and Cys 311 of the hIP to Ser 309 and Ser 311 was performed using pHM-hIP C309S as a template and the oligonucleotide primers: 5Ј-GTC TGC AGC CTG AGC CTC GGG CCT G-3Ј (sense primer) and 5Ј-C AGG CCC GAG GCT CAG GCT (20,26). The plasmids pCMV-G␣ q , pCMV-G␣ s , and pHM:HaRas have been previously described (18,20,25,26).…”

Section: C311smentioning

confidence: 99%

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Palmitoylation of the Human Prostacyclin Receptor

Miggin

Lawler

Kinsella

2003

Journal of Biological Chemistry

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, nor hIP C308S,C309S,C311S coupled to G q . Taken together, these data confirm that the hIP is isoprenylated and palmitoylated, and collectively these modifications modulate its G protein coupling and effector signaling. We propose that through lipid modification followed by membrane insertion, the C-tail domain of the IP may contain a double loop structure anchored by the dynamically regulated palmitoyl groups proximal to transmembrane domain 7 and by a distal farnesyl isoprenoid permanently attached to its carboxyl terminus.Modification of proteins through the covalent attachment of lipid groups occurs within a wide variety of cellular proteins and may be involved in mediating protein-membrane and/or protein-protein interactions (1-3). Three of the most common lipid modifications are N-myristoylation, isoprenylation and thio(S)-acylation. In contrast to myristoylation and isoprenylation, which typically occur either as co-translational or as immediate post-translational events, S-acylation through attachment of palmitate to Cys residue(s), via a labile thioester bond, occurs post-translationally (1). Moreover, whereas the former two modifications remain attached until protein degradation, palmitoylation is a reversible, dynamic modification that turns over more rapidly than the protein itself and thus has the potential to be regulated (2, 3). A diverse family of cellular proteins are established to be palmitoylated including ␣ subunits of the heterotrimeric G protein subunits, for example G␣ s and G␣ q , Ha-and N-Ras proteins, A kinase anchoring protein 15 and 18, endothelial nitric-oxide synthase, adenylyl cyclase, G protein-coupled receptor kinases 4 and 6, diverse members of the Src family of nonreceptor tyrosine kinases, in addition to several members of the G protein-coupled receptor (GPCR)

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Superfamily (1 2 4 5)mentioning

confidence: 99%

Section: C311smentioning

confidence: 99%

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Palmitoylation of the Human Prostacyclin Receptor

Miggin

Lawler

Kinsella

2003

Journal of Biological Chemistry

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“…Instead, it serves to reprogram the G protein-coupling specificity of the ␤ 2 AR such that it couples less well to G s (desensitization) and can now couple to G i (2)(3)(4)(5). Such switching mechanisms have also been described for the vasoactive intestinal peptide (38) and prostacyclin receptors (39,40). Arrestin serves as an agonistrecruitable signaling scaffold protein (9).…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from G _s to G _i

Baillie

Sood

McPhee

et al. 2003

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

344

356

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Phosphorylation of the ␤2 adrenoreceptor (␤2AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory protein (Gs) to inhibitory guanine nucleotide regulatory protein (G i). ␤-Arrestins recruit the cAMP-degrading PDE4 phosphodiesterases to the ␤2AR, thus controlling PKA activity at the membrane. Here we investigate a role for PDE4 recruitment in regulating G protein switching by the ␤2AR. In human embryonic kidney 293 cells overexpressing a recombinant ␤2AR, stimulation with isoprenaline recruits ␤-arrestins 1 and 2 as well as both PDE4D3 and PDE4D5 to the receptor and stimulates receptor phosphorylation by PKA. The PKA phosphorylation status of the ␤2AR is enhanced markedly when cells are treated with the selective PDE4-inhibitor rolipram or when they are transfected with a catalytically inactive PDE4D mutant (PDE4D5-D556A) that competitively inhibits isoprenaline-stimulated recruitment of native PDE4 to the ␤2AR. Rolipram and PDE4D5-D556A also enhance ␤2AR-mediated activation of extracellular signal-regulated kinases ERK1͞2. This is consistent with a switch in coupling of the receptor from G s to Gi, because the ERK1͞2 activation is sensitive to both inhibitors of PKA (H89) and G i (pertussis toxin). In cardiac myocytes, the ␤2AR also switches from G s to Gi coupling. Treating primary cardiac myocytes with isoprenaline induces recruitment of PDE4D3 and PDE4D5 to membranes and activates ERK1͞2. Rolipram robustly enhances this activation in a manner sensitive to both pertussis toxin and H89. Adenovirus-mediated expression of PDE4D5-D556A also potentiates ERK1͞2 activation. Thus, receptor-stimulated ␤-arrestinmediated recruitment of PDE4 plays a central role in the regulation of G protein switching by the ␤2AR in a physiological system, the cardiac myocyte.

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Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases

Kveberg¹,

Bryceson²,

Inngjerdingen³

et al. 2002

Eur. J. Immunol.

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We have examined the effect of sphingolipids on the chemotaxis of human natural killer (NK) cells. Messenger RNA for Edg‐1, Edg‐6 and Edg‐8 but not Edg‐3, are expressed in these cells. Sphingosine 1 phosphate (SPP), dihydro SPP (DHSPP) or the CC chemokine RANTES (CCL5), but not sphingosine induces the chemotaxis of these cells. Pertussis toxin inhibits the chemotaxis induced by these ligands. Permeabilization of NK cells with streptolysin O (SLO) and introduction of blocking antibodies to the heterotrimeric G proteins, showed that Gαi2, Gαs, Gαq/11 or Gα13 mediate the chemotaxis of SPP, whereas Gαi2, Gαo or Gαq/11 mediate the chemotaxis of DHSPP. Gαi2, Gαo, Gαs, Gαq/11, Gαz or Gα12 mediates RANTES‐induced NK cell chemotaxis. Further analysis showed that phosphoinositide 3 kinase (PI3K) inhibitors wortmannin and LY294002 inhibit NK cell chemotaxis induced by SPP, DHSPP or RANTES. Blocking antibody to PI3Kγ inhibits the chemotaxis induced by the three ligands, whereas anti‐PI3Kβ was without effect. In contrast, SPP and DHSPP recruit PI3Kβ isozyme into NK cell membranes, suggesting that although this isoform is not involved in chemotaxis, it is activated by these phospholipids.

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Protein Kinase A-mediated Phosphorylation of Serine 357 of the Mouse Prostacyclin Receptor Regulates Its Coupling to Gs-, to Gi-, and to Gq-coupled Effector Signaling

Cited by 113 publications

References 42 publications

Palmitoylation of the Human Prostacyclin Receptor

Palmitoylation of the Human Prostacyclin Receptor

RETRACTED: β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from G _s to G _i

Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases

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Protein Kinase A-mediated Phosphorylation of Serine 357 of the Mouse Prostacyclin Receptor Regulates Its Coupling to Gs-, to Gi-, and to Gq-coupled Effector Signaling

Cited by 113 publications

References 42 publications

Palmitoylation of the Human Prostacyclin Receptor

Palmitoylation of the Human Prostacyclin Receptor

RETRACTED: β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from G s to G i

Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases

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RETRACTED: β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from G _s to G _i