A New Pathway for Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Signaling

Ehses, Jan A.; Lee, Shelter S.T.; Pederson, Raymond A.; McIntosh, Christopher H.S.

doi:10.1074/jbc.m103023200

Cited by 51 publications

(11 citation statements)

References 60 publications

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“…Analogues resulting from the connection of (1-14) and (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) domains by one or two Ahx residues (analogues 13 and 14, respectively) showed noticeable increases in cAMP production with EC 50 values in the low micromolar range, similar to analogues 4 and 6 (Table 2, Figure 2A). The introduction of an extra Ahx residue (analogue 15) resulted in nearly complete loss of ability to stimulate cAMP production, perhaps because of excessive conformational freedom induced by three successive aminohexanoic acids ( Figure 2A).…”

Section: Resultsmentioning

confidence: 51%

Structure−Function Analysis of a Series of Novel GIP Analogues Containing Different Helical Length Linkers

et al. 2003

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Glucose-dependent insulinotropic polypeptide (GIP1-42) is a potent glucose-lowering intestinal peptide hormone. The equipotent GIP1-30NH2 was structurally modified by linking N- and C-terminal fragments with several different linkers. Substitution of the middle region of GIP by a flexible aminohexanoic linker resulted in greatly reduced binding affinity and reduction or complete loss of bioactivity. Connection of the bioactive domains GIP1-14 and GIP19-30NH2 by EKEK or AAAA linkers resulted in peptide agonists with approximately 3-4-fold increased bioactivity as compared to GIP1-30NH2. Conformational analysis by CD spectroscopy of GIP fragments and analogues suggests a helical region in the C-terminal (19-30) portion of GIP. It was demonstrated that stabilization of this C-terminal helical region by the introduction of helical linkers favored binding and activation of the GIP receptor. Our results suggest an important contribution of a direct interaction of the first 14 amino acids with the GIP receptor, an appropriate relative orientation of N- and C-terminal parts of GIP, and the presence of helical linkers to be essential for bioactivity.

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Section: Resultsmentioning

confidence: 51%

Structure−Function Analysis of a Series of Novel GIP Analogues Containing Different Helical Length Linkers

et al. 2003

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“…An intervening peptide (C terminus of ␤-adrenergic receptor kinase) that we previously employed to investigate GIP signaling (38) was expressed in increasing amounts in rGIP-15 cells, but it was unable to reverse 1 nM GIP-mediated activation of ERK1/2 phosphorylation (Fig. 8), thus providing evidence against a role for G␤␥ signaling in ERK1/2 regulation.…”

Section: Gip Activates Erk Via Rap1 Independently Of G␤␥ and Src-mentioning

confidence: 97%

“…Supportive studies with a third ␤-cell line, Brin-D11, also mimic these actions of GIP (data not shown). GIP signals via cAMP and arachidonic acid (AA) in rGIP-15 cells and ␤-cell lines (5,38). To identify the proximal regulator of the ERK module, we tested the ability of these two second messengers to modulate ERK1/2 phosphorylation, while using the phorbol ester, phorbol myristic acid (PMA), as a positive control for ERK1/2 activation (Fig.…”

Section: and Ins-1 (832/13) Ranked As Highly Expressedmentioning

confidence: 99%

Glucose-dependent Insulinotropic Polypeptide Activates the Raf-Mek1/2-ERK1/2 Module via a Cyclic AMP/cAMP-dependent Protein Kinase/Rap1-mediated Pathway

Ehses

Pelech

Pederson

et al. 2002

Journal of Biological Chemistry

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115

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The gastrointestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is one of the most important regulators of insulin secretion following ingestion of a meal. GIP stimulates insulin secretion from the pancreatic ␤-cell via its G protein-coupled receptor activation of adenylyl cyclase and other signal transduction pathways, but there is little known regarding subsequent protein kinase pathways that are activated. A screening technique was used to determine the relative abundance of 75 protein kinases in CHO-K1 cells expressing the GIP receptor and in two pancreatic ␤-cell lines (␤TC-3 and INS-1 (832/13) cells). This information was used to identify kinases that are potentially regulated following GIP stimulation, with a focus on GIP regulation of the ERK1/2 MAPK pathway. In CHO-K1 cells, GIP induced phosphorylation of Raf-1 (Ser-259), Mek1/2 (Ser-217/Ser-221), ERK1/2 (Thr-202 and Tyr-204), and p90 RSK (Ser-380) in a concentration-dependent manner. Activation of ERK1/2 was maximal at 4 min and was cAMP-dependent protein kinase-dependent and protein kinase C-independent. Studies using a ␤-cell line (INS-1 clone 832/13) corroborated these findings, and it was also demonstrated that the ERK1/2 module could be activated by GIP in the absence of glucose. Finally, we have shown that GIP regulation of the ERK1/2 module is via Rap1 but does not involve G␤␥ subunits nor Src tyrosine kinase, and we propose that cAMP-based regulation occurs via B-Raf in both CHO-K1 and ␤-cells. These results establish the importance of GIP in the cellular regulation of the ERK1/2 module and identify a role for cAMP in coupling its G protein-coupled receptors to ERK1/2 activity in pancreatic ␤-cells.

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“…In GC cells, sst 2 receptors that are coupled to [Ca 2+ ] i control, modulate cAMP pathways, whereas sst 1 receptors are coupled to phospholipase A 2 pathways independently of [Ca 2+ ] i control [15]. Since the phospholipase A 2 pathway is involved in secretory events in different experimental models [37, 38, 39], it is tempting to speculate that the inhibition of this pathway may be also responsible for the sst 1 control of GH secretion in GC cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Control of Growth Hormone Secretion by Somatostatin in Rat Pituitary GC Cells: sst<sub>2</sub> but Not sst<sub>1</sub> Receptors Are Coupled to Inhibition of Single-Cell Intracellular Free Calcium Concentrations

Cervia

Petrucci²,

Bluet-Pajot³

et al. 2002

Neuroendocrinology

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Rat pituitary tumor cells (GC cells) exhibit spontaneous oscillations of intracellular free calcium concentration ([Ca²⁺]_i) that allow continuous release of growth hormone (GH). Of the somatostatin (SRIH) receptor subtypes (sst receptors) mediating SRIH action, sst₁ and sst₂ receptors are highly expressed by GC cell membranes. In the present study, the effects of sst₁ or sst₂ receptor activation on single-cell [Ca²⁺]_i were investigated in GC cells by confocal fluorescence microscopy. In addition, the effects of sst₁ or sst₂ receptor activation on GH secretion were also studied. Our results demonstrate that SRIH decreases [Ca²⁺]_i baseline and almost completely blocks Ca²⁺ transients through activation of sst₂ but not of sst₁ receptors. In contrast, SRIH effectively inhibits GH secretion through activation of both sst₁ and sst₂ receptors. Blocking Ca²⁺ transients is less efficient than SRIH to inhibit GH release. The cyclic octapeptide, CYN-154806, antagonizes sst₂ receptors at [Ca²⁺]_i since it abolishes the sst₂ receptor-mediated inhibition of [Ca²⁺]_i without affecting single-cell Ca²⁺ signals. On the other hand, CYN-154806 alone potently inhibits GH secretion through the involvement of pertussis toxin-sensitive G proteins. In conclusion, the present results demonstrate that SRIH inhibition of GH release in GC cells involves mechanisms either dependent or independent on SRIH modulation of [Ca²⁺]_i. The implications of CYN-154806 inhibition of GH secretion are discussed.

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A New Pathway for Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Signaling

Cited by 51 publications

References 60 publications

Structure−Function Analysis of a Series of Novel GIP Analogues Containing Different Helical Length Linkers

Structure−Function Analysis of a Series of Novel GIP Analogues Containing Different Helical Length Linkers

Glucose-dependent Insulinotropic Polypeptide Activates the Raf-Mek1/2-ERK1/2 Module via a Cyclic AMP/cAMP-dependent Protein Kinase/Rap1-mediated Pathway

Inhibitory Control of Growth Hormone Secretion by Somatostatin in Rat Pituitary GC Cells: sst<sub>2</sub> but Not sst<sub>1</sub> Receptors Are Coupled to Inhibition of Single-Cell Intracellular Free Calcium Concentrations

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