Non-genomic mechanisms mediate androgen-induced PSD95 expression

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Non-genomic actions of androgens influence synaptic plasticity, but mechanisms are debated.
• Testosterone-fetal bovine serum albumin (T-BSA) rapidly increases postsynaptic density 95 (PSD95) protein via transcription-independent pathways.

Purpose of the Study:

• To elucidate the specific membrane-binding sites and signaling pathways mediating T-BSA-induced PSD95 expression.
• To differentiate the roles of membrane androgen receptors versus other membrane proteins in androgen signaling.

Main Methods:

• Utilized T-BSA conjugated with FITC to identify membrane androgen-binding sites.
• Investigated the involvement of G-protein-coupled receptor (GPCR)-zinc transporter ZIP9 (SLC39A9) in T-BSA signaling.
• Examined the interaction between ZIP9 and Gnα11, and the subsequent phosphorylation of Erk1/2 MAPK and eIF4E.
• Assessed the impact of ZIP9 or Gnα11 knockdown and Erk1/2 inhibition on PSD95 and p-eIF4E levels.

Main Results:

• Verified membrane androgen-binding sites using T-BSA-FITC.
• Demonstrated that T-BSA-induced PSD95 expression is mediated by ZIP9, not membrane androgen receptors.
• Showed T-BSA promotes ZIP9 interaction with Gnα11, leading to Erk1/2 and eIF4E phosphorylation.
• Confirmed that ZIP9/Gnα11 knockdown or Erk1/2 inhibition reduces PSD95 and p-eIF4E expression.

Conclusions:

• ZIP9 mediates the non-genomic effects of androgens on PSD95 synthesis through the Gnα11/Erk1/2/eIF4E pathway in HT22 cells.
• This identifies a novel mechanism for androgen action on synaptic protein synthesis.
• Provides a basis for understanding the neuroprotective roles of androgens.