Abstract
The non-genomic actions of androgen-induced synaptic plasticity have been extensively studied. However, the underlying mechanisms remain controversial. We recently found that testosterone-fetal bovine serum albumin (T-BSA), a cell membrane-impermeable complex, led to a rapid increase in the postsynaptic density 95 (PSD95) protein level through a transcription-independent mechanism in mouse hippocampal HT22 cells. Using T-BSA conjugated FITC, we verified the presence of membrane androgen-binding sites. Here, we show that T-BSA-induced PSD95 expression is mediated by G-protein-coupled receptor (GPCR)-zinc transporter ZIP9 (SLC39A9), one of the androgen membrane binding sites, rather than the membrane-localized androgen receptor. Furthermore, we found that T-BSA induced an interaction between ZIP9 and Gnα11 that lead to the phosphorylation of Erk1/2 MAPK and eIF4E, which are critical in the mRNA translation process. The PSD95 and p-eIF4E expression decreased when knockdown of ZIP9 or Gnα11 expression or inhibition of Erk1/2 activation. Taken together, these findings suggest that ZIP9 mediates the non-genomic action of androgen on synaptic protein PSD95 synthesis through the Gnα11/Erk1/2/eIF4E pathway in HT22 cells. This novel mechanism provides a theoretical basis to understand the neuroprotective mechanism of androgen.
Highlights
Age-related hormonal changes are associated with cognitive impairment in various neurodegenerative diseases such as Alzheimer’s disease (AD) [1, 2]
We show that testosterone‐fetal bovine serum albumin (T‐BSA)‐induced postsynaptic density 95 (PSD95) expression is mediated by G‐protein‐coupled receptor (GPCR)‐zinc transporter ZIP9 (SLC39A9), one of the androgen membrane binding sites, rather than the membrane‐ localized androgen receptor
We found that T‐BSA induced an interaction between ZIP9 and Gnα11 that lead to the phosphorylation of Erk1/2 mitogen-activated protein kinase (MAPK) and eIF4E, which are critical in the mRNA translation process
Summary
Age-related hormonal changes are associated with cognitive impairment in various neurodegenerative diseases such as Alzheimer’s disease (AD) [1, 2]. Animal and cellular models have been used to explore the mechanism underlying this relationship between androgen deficiency and AD. In this regard, androgen deficiency leads to an increase in β-amyloid plaques and neurofibrillary tangles, which are the 2 major pathological hallmarks in AD patients [1]. Previous studies have www.aging‐us.com demonstrated that testosterone supplementation rapidly increases the dendritic spine density of hippocampal neurons in male rats [9,10,11]. Our previous in vivo study has revealed that testosterone rapidly increases PSD95 expression along with dendritic spine density in the hippocampus of the senescence-accelerated mouse prone 8 (SAMP8) line [12], which is a naturally occurring mouse line that displays a phenotype of accelerated aging. Increasing the expression of Dlg4/PSD95 through epigenetic mechanisms rescued learning and memory deficits in aged and Alzheimer’s disease mice [16]
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