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Phosphorylation and transcriptional activity regulation of retinoid‐related orphan receptor alpha 1 by protein kinases C

Retinoid‐related orphan receptor α1 (RORα1) is a member of the nuclear receptor superfamily. It is highly expressed in CNS particularly in the cerebellum. Absence of this transcription factor in mice leads to several abnormalities, such as cerebellar atrophy linked to Purkinje cell death and impaired differentiation. A major role of RORα1 in neuronal survival is the control of reactive oxygen species homeostasis. RORα1 is a constitutively active receptor, but its regulation is yet not well known. Protein kinase C (PKC) also plays a major role in neuronal survival and differentiation, suggesting its possible involvement in post‐translational modifications and regulation of RORα1 transcriptional activity. To test this hypothesis, we over‐expressed the human isoform of this nuclear receptor in cortical neurons and COS‐7 cells, which were then treated with different effectors acting on PKC activity. We showed for the first time that conventional PKCs induce phosphorylation and inhibition of RORα1 activity. We also investigated mitogen‐activated protein kinase/extracellular signal‐regulated kinase (1/2) involvement in this effect. Our results bring new insights into the control of RORα1 activity and highlight its importance in further investigations of the mechanisms involved in neuronal cell death in neurodegenerative diseases.