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PMID:19057895

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Citation

Knauer, CS, Campbell, JE, Chio, CL and Fitzgerald, LW (2009) Pharmacological characterization of mitogen-activated protein kinase activation by recombinant human 5-HT2C, 5-HT2A, and 5-HT2B receptors. Naunyn Schmiedebergs Arch. Pharmacol. 379:461-71

Abstract

The type 2 serotonin (5-HT(2)) receptor subfamily is known to couple to phosphoinositide hydrolysis (PI) and the subsequent mobilization of intracellular Ca(2+), as well as the release of arachidonic acid (AA). Less is known of 5-HT(2)-mediated activation of the mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase (ERK1/2) signaling. The present study measured the relative efficacies and potencies of 5-HT agonists to activate ERK2 in non-neuronal cells expressing recombinant human 5-HT(2A), 5-HT(2B), and 5-HT(2C(ISV)) receptors. 5-HT agonists stimulated ERK2 activity via all three 5-HT(2) subtypes. There were no meaningful differences in the potencies or relative efficacies of these agonists to affect ERK2 activity vs. PI accumulation or Ca(2+) mobilization, suggesting that these pathways may be sequentially linked. Indeed, ERK2 activity was very sensitive to PKC inhibition and calcium chelation and insensitive to tyrosine kinase and PI-3-kinase inhibition. 5-HT(2) receptors efficiently couple to MAPK activation via sequential PI hydrolysis, and Ca(2+) mobilization. This profile differs from reports of "agonist-directed trafficking of receptor stimulus" between PI/Ca(2+) and AA pathways activated by 5-HT(2) receptors.

Links

PubMed Online version:10.1007/s00210-008-0378-4

Keywords

Animals; Blotting, Western; CHO Cells; Calcium/metabolism; Cricetinae; Cricetulus; Enzyme Activation; Humans; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Phosphatidylinositols/metabolism; Protein Binding; Radioligand Assay; Receptor, Serotonin, 5-HT2A/biosynthesis; Receptor, Serotonin, 5-HT2A/physiology; Receptor, Serotonin, 5-HT2B/biosynthesis; Receptor, Serotonin, 5-HT2B/physiology; Receptor, Serotonin, 5-HT2C/biosynthesis; Receptor, Serotonin, 5-HT2C/physiology; Recombinant Proteins/biosynthesis; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:5HT2A

involved_in

GO:0006874: cellular calcium ion homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2A

involved_in

GO:0010513: positive regulation of phosphatidylinositol biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2A

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2A

enables

GO:0051378: serotonin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:5HT2A

enables

GO:0071886: 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:5HT2B

involved_in

GO:0007202: activation of phospholipase C activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2B

involved_in

GO:0006874: cellular calcium ion homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2B

involved_in

GO:0010513: positive regulation of phosphatidylinositol biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2B

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2B

enables

GO:0051378: serotonin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:5HT2C

involved_in

GO:0006874: cellular calcium ion homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2C

involved_in

GO:0010513: positive regulation of phosphatidylinositol biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2C

enables

GO:0051378: serotonin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:5HT2C

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2C

enables

GO:0071886: 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

Notes

See also

References

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