Docosahexaenoic Acid (DHA) Induced Morphological Differentiation of Astrocytes Is Associated with Transcriptional Upregulation and Endocytosis of β₂-AR.

Docosahexaenoic acid (DHA), an important ω-3 fatty acid, is abundantly present in the central nervous system and is important in every step of brain development. Much of this knowledge has been based on studies of the role of DHA in the function of the neurons, and reports on its effect on the glial cells are few and far between. We have previously reported that DHA facilitates astrocyte differentiation in primary culture. We have further explored the signaling mechanism associated with this event. It was observed that a sustained activation of the extracellular signal-regulated kinase (ERK) appeared to be critical for DHA-induced differentiation of the cultured astrocytes. Prior exposure to different endocytic inhibitors blocked both ERK activation and differentiation of the astrocytes during DHA treatment suggesting that the observed induction of ERK-2 was purely endosomal. Unlike the β₁-adrenergic receptor (β₁-AR) antagonist, atenolol, pre-treatment of the cells with the β₂-adrenergic receptor (β₂-AR) antagonist, ICI-118,551 inhibited the DHA-induced differentiation process, indicating a downstream involvement of β₂-AR in the differentiation process. qRT-PCR and western blot analysis demonstrated a significant induction in the mRNA and protein expression of β₂-AR at 18-24 h of DHA treatment, suggesting that the induction of β₂-AR may be due to transcriptional upregulation. Moreover, DHA caused activation of at 6 h, followed by activation of downstream cAMP response element-binding protein, a known transcription factor for β₂-AR. Altogether, the observations suggest that DHA upregulates β₂-AR in astrocytes, which undergo endocytosis and signals for sustained endosomal ERK activation to drive the differentiation process.

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