Coupling of Serotonin 5‐HT_1B Receptors to Activation of Mitogen‐Activated Protein Kinase (ERK‐2) and p70 S6 Kinase Signaling Systems

Abstract

Little is known about the coupling of serotonin 5‐HT1B receptors to cellular signals other than cyclic AMP. In the present studies, the activation by 5‐HT1B receptors of p70 S6 kinase and the mitogen‐activated protein kinase (MAP kinase) ERK‐2 was investigated. Studies were performed by using both nontransfected Chinese hamster ovary (CHO) cells, which express endogenous receptors at a very low density, and a stable transfected CHO cell line expressing 5‐HT1B receptors at 230 fmol/mg of membrane protein, a density similar to that expressed in cortex. In nontransfected cells, 5‐HT was found to stimulate a greater than twofold increase in MAP kinase activity with an EC50 of 20 nM. Reflecting increased density of receptors, 5‐HT caused a greater than eightfold activation of ERK‐2 in transfected cells with an EC50 of 2 nM. 5‐HT was found to also stimulate p70 S6 kinase in both nontransfected and transfected cells. The stimulation was sixfold in both types of cells, but the EC50 for 5‐HT was fourfold lower in transfected cells. The coupling of 5‐HT1B receptors to ERK‐2 and to p70 S6 kinase was inhibited by pertussis toxin, inhibitors of phosphatidylinositol 3‐kinase, and by the inhibitor of MAP kinase kinase PD098059. Activation of p70 S6 kinase, but not ERK‐2, was also inhibited by rapamycin. These findings demonstrate that 5‐HT1B receptors couple to ERK‐2 and p70 S6 kinase through overlapping, but nonidentical, pathways.

Serotonin-Induced Growth of Pulmonary Artery Smooth Muscle Requires Activation of Phosphatidylinositol 3-Kinase/Serine-Threonine Protein Kinase B/Mammalian Target of Rapamycin/p70 Ribosomal S6 Kinase 1

“…However, except in limited studies with neuronal cells (17), this pathway has not been explored in relation to 5-HT-induced cellular responses. In the case of the neuronal cells, the 5-HT 1B receptor was coupled to pathway activation, and cellular proliferation as an end product was not investigated.…”

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“…In a previous study, the p70S6 kinase was shown to couple with 5-HT1B receptor [36], therefore we explored the effects on the three specific phosphorylation for the p70S6 kinase; phospho-p70S6 kinase (Thr389), phospho-p70S6 kinase (Thr421, Ser424) or phospho-p44/42 MAPK (p-ERK1/2) (Thr202/ Tyr204), using western blotting.…”

Role of Serotonin Type-1A/B (Hydroxytryptamine) Receptors in Depression Revisited

“…In the subsequent steps, other proteins and downstream mediators like p70, S6 are involved that activate mitogen activated proteins leading to activation of CREB like molecules that are responsible for regulating the transcription. [82,83] …”