Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation

Author(s)

Greenwood, Michael P. ^[1] ; Greenwood, Mingkwan ^[1] ; Mecawi, Andre S. ^{[2, 3, 4]} ; Antunes-Rodrigues, Jose ^[2] ; Paton, Julian F. R. ^[5] ; Murphy, David ^{[1, 3]}

Affiliation

^[1] Univ Bristol, Sch Clin Sci, Bristol BS1 3NY, Avon - England

^[2] Univ Sao Paulo, Sch Med Ribeirao Preto, BR-14049 Ribeirao Preto - Brazil

^[3] Univ Malaya, Dept Physiol, Kuala Lumpur 50603 - Malaysia

^[4] Univ Fed Rural Rio de Janeiro, Inst Biol, Dept Physiol Sci, Rio De Janeiro - Brazil

^[5] Univ Bristol, Sch Physiol & Pharmacol, Bristol BS8 1TD, Avon - England

• Document type: Journal article
• Source: MOLECULAR BRAIN; v. 9, JAN 7 2016.
• Web of Science Citations: 6

Abstract

Background: Rasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain. Results: We show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress. Conclusions: We have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain. (AU)

• FAPESP's process: 11/52108-4 - Behavioural and neuroendocrine mechanisms regulating hydromineral metabolism: a lifelong perpective
• Grantee: José Antunes Rodrigues
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/09799-1 - Energy balance and body fluid homeostasis control: from cells to the physiological systems
• Grantee: José Antunes Rodrigues
• Support Opportunities: Research Projects - Thematic Grants