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Serotonin regulates 6-phosphofructo-1-kinase activity in a PLC–PKC–CaMK II- and Janus kinase-dependent signaling pathway

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Abstract

Serotonin (5-HT) is a hormone that has been implicated in the regulation of many physiological and pathological events. One of the most intriguing properties of this hormone is its ability to up-regulate mitosis. Moreover, 5-HT stimulates glucose uptake and up-regulates PFK activity through the 5-HT2A receptor, resulting in the phosphorylation of a tyrosine residue of PFK and the intracellular redistribution of PFK within skeletal muscle. The present study investigated some of the signaling intermediates involved in the effects of 5-HT on 6-phosphofructo-1-kinase (PFK) regulation from skeletal muscle using kinetic assessments, immunoprecipitation, and western blotting assays. Our results demonstrate that 5-HT stimulates PFK from skeletal muscle via phospholipase C (PLC). The activation of PLC in skeletal muscle leads to the recruitment of protein kinase C (PKC) and calmodulin and the stimulation of calmodulin kinase II, which associates with PFK upon 5-HT action. Alternatively, 5-HT loses its ability to up-regulate PFK activity when Janus kinase is inhibited, suggesting that 5-HT is able to control glycolytic flux in the skeletal muscle of mice by recruiting different pathways and controlling PFK activity.

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Abbreviations

5-HT:

5-Hydroxytryptamine, serotonin

CaMK II:

Calcium–calmodulin-dependent protein kinase type II

f-actin:

Filamentous actin

F6P:

Fructose-6-phosphate

GLUT:

Glucose transporter

GPCRs:

G-protein-coupled receptors

KN-62:

1-[N,O-Bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine

PFK:

6-Phosphofructo-1-kinase

PI3 K:

Phosphatidylinositol-3-phosphate kinase

PKC:

Protein kinase C

PLC:

Phospholipase C

PMA:

Phorbol-12-myristate-13-acetate

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Acknowledgments

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Programa de Oncobiologia) and Programa de Núcleos de Excelência (PRONEX).

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  1. Laboratório de Enzimologia e Controle do Metabolismo (LabECoM), Departamento de Fármacos, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ, 21941-590, Brazil

    Wagner Santos Coelho & Mauro Sola-Penna

  2. Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Wagner Santos Coelho

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  1. Wagner Santos Coelho
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Correspondence to Mauro Sola-Penna.

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Coelho, W.S., Sola-Penna, M. Serotonin regulates 6-phosphofructo-1-kinase activity in a PLC–PKC–CaMK II- and Janus kinase-dependent signaling pathway. Mol Cell Biochem 372, 211–220 (2013). https://doi.org/10.1007/s11010-012-1462-0

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