Identification of dual mechanisms mediating 5-hydroxytryptamine receptor 1F-induced mitochondrial biogenesis

Am J Physiol Renal Physiol. 2018 Feb 1;314(2):F260-F268. doi: 10.1152/ajprenal.00324.2017. Epub 2017 Oct 18.

Abstract

Our laboratory recently made the novel observation that 5-hydroxytryptamine 1F (5-HT1F) receptor activation induces mitochondrial biogenesis (MB), the production of new, functional mitochondria, in vitro and in vivo. We sought to determine the mechanism linking the 5-HT1F receptor to MB in renal proximal tubule cells. Using LY344864 , a selective 5-HT1F receptor agonist, we determined that the 5-HT1F receptor is coupled to Gαi/o and induces MB through Gβγ-dependent activation of Akt, endothelial nitric oxide synthase (eNOS), cyclic guanosine-monophosphate (cGMP), protein kinase G (PKG), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). We also report that the 5-HT1F receptor signals through a second, Gβγ-dependent pathway that is linked by Akt phosphorylation of Raf. In contrast to the activated Akt pathway, Raf phosphorylation reduced extracellular signal regulated kinases (ERK1/2) and foxhead box O3a (FOXO3a) phosphorylation, suppressing an inhibitory MB pathway. These results demonstrate that the 5-HT1F receptor regulates MB through Gβγ-dependent dual mechanisms that activate a stimulatory MB pathway, Akt/eNOS/cGMP/PKG/PGC-1α, while simultaneously repressing an inhibitory MB pathway, Raf/MEK/ERK/FOXO3a. Novel mechanisms of MB provide the foundation for new chemicals that induce MB to treat acute and chronic organ injuries.

Keywords: 5-HT; Akt; ERK; G protein-coupled receptor; GPCR; extracellular signal regulated kinase; mitochondria; protein kinase B; serotonin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carbazoles / pharmacology
  • Cells, Cultured
  • Female
  • Fluorobenzenes / pharmacology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Organelle Biogenesis*
  • Phosphorylation
  • Rabbits
  • Receptor, Serotonin, 5-HT1F
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism*
  • Second Messenger Systems
  • Serotonin 5-HT1 Receptor Agonists / pharmacology

Substances

  • Carbazoles
  • Fluorobenzenes
  • Intracellular Signaling Peptides and Proteins
  • LY 344864
  • Receptors, Serotonin
  • Serotonin 5-HT1 Receptor Agonists