scholarly journals Ras-GRF1 in CRF Cells Controls the Early Adolescent Female Response to Repeated Stress

2020 ◽  
Author(s):  
Shan-xue Jin ◽  
David A. Dickson ◽  
Jamie Maguire ◽  
Larry A. Feig
Keyword(s):  
Hippocampal Neurons ◽  
Restraint Stress ◽  
Early Adolescent ◽  
Adolescent Female ◽  
Nucleotide Exchange ◽  
Control Male ◽  
Female Mice ◽  
Repeated Stress ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

ABSTRACTRas-GRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates Ras and Rac GTPases. In hippocampal neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed that GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after exposure to 7-days of restraint-stress (7DRS) (30 min/day) elevation of serum CORT levels are suppressed in early adolescent (EA) female, but not EA male or adult female GRF1 knockdown mice. Here, we show that this phenotype is due, at least in part, to the loss of GRF1 expression in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockdown specifically in these cells also reduces serum CORT response to 7DRS in EA females, but not EA males or adult females. Moreover, it reduces females CORT levels to those to found in comparably stressed control male mice. GRF1 knockdown in CRF cells also blocks the anxiolytic phenotype normally found in EA females 24 hrs after 7DRS. Interestingly, loss of GRF1 in these cells has no effect after only 3 exposures to restraint stress, revealing a role for GRF1 in repeated stress-induced CRF cell plasticity that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response early-adolescent female display to repeated stress.

scholarly journals RASGRF1 in CRF cells controls the early adolescent female response to repeated stress

2020 ◽  
Vol 245 (3) ◽  
pp. 397-410
Author(s):  
Shan-xue Jin ◽  
David A Dickson ◽  
Jamie Maguire ◽  
Larry A Feig
Keyword(s):  
Restraint Stress ◽  
Elevated Serum ◽  
Early Adolescent ◽  
Nucleotide Exchange ◽  
Female Response ◽  
Female Mice ◽  
Repeated Stress ◽  
Guanine Nucleotide Exchange ◽  
Rac Gtpases ◽  
Nucleotide Exchange Factor

RASGRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates RAS and RAC GTPases. In hippocampus neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after 7 days of restraint stress (7DRS) (30 min/day) both elevated serum CORT levels and induction of an anxiolytic phenotype normally observed in early adolescent (EA) female mice are blocked in GRF1-knockout mice. In contrast, no effects were observed in EA male or adult females. Here, we show this phenotype is due, at least in part, to GRF1 loss in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockout specifically in these cells suppressed 7DRS-induced elevation of serum CORT levels specifically in EA females, but only down to levels found in comparably stressed EA males. Nevertheless, it still completely blocked the 7DRS-induced anxiolytic phenotype observed in EA females. Interestingly, loss of GRF1 in CRF cells had no effect after only three restraint stress exposures, implying a role for GRF1 in 7DRS stress-induced plasticity of CRF cells that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response EA females display to repeated stress.

ACAP3 regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons

2016 ◽  
Vol 473 (17) ◽  
pp. 2591-2602 ◽  
Author(s):  
Yuki Miura ◽  
Tsunaki Hongu ◽  
Yohei Yamauchi ◽  
Yuji Funakoshi ◽  
Naohiro Katagiri ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Hippocampal Neurons ◽  
Coiled Coil ◽  
Small Gtpase ◽  
Nucleotide Exchange ◽  
Wild Type ◽  
Guanine Nucleotide Exchange ◽  
Gtpase Activating Proteins ◽  
Nucleotide Exchange Factor ◽  
Adp Ribosylation Factor

ACAP3 (ArfGAP with coiled-coil, ankyrin repeat and pleckstrin homology domains 3) belongs to the ACAP family of GAPs (GTPase-activating proteins) for the small GTPase Arf (ADP-ribosylation factor). However, its specificity to Arf isoforms and physiological functions remain unclear. In the present study, we demonstrate that ACAP3 plays an important role in neurite outgrowth of mouse hippocampal neurons through its GAP activity specific to Arf6. In primary cultured mouse hippocampal neurons, knockdown of ACAP3 abrogated neurite outgrowth, which was rescued by ectopically expressed wild-type ACAP3, but not by its GAP activity-deficient mutant. Ectopically expressed ACAP3 in HEK (human embryonic kidney)-293T cells showed the GAP activity specific to Arf6. In support of this observation, the level of GTP-bound Arf6 was significantly increased by knockdown of ACAP3 in hippocampal neurons. In addition, knockdown and knockout of Arf6 in mouse hippocampal neurons suppressed neurite outgrowth. These results demonstrate that ACAP3 positively regulates neurite outgrowth through its GAP activity specific to Arf6. Furthermore, neurite outgrowth suppressed by ACAP3 knockdown was rescued by expression of a fast cycle mutant of Arf6 that spontaneously exchanges guanine nucleotides on Arf6, but not by that of wild-type, GTP- or GDP-locked mutant Arf6. Thus cycling between active and inactive forms of Arf6, which is precisely regulated by ACAP3 in concert with a guanine-nucleotide-exchange factor(s), seems to be required for neurite outgrowth of hippocampal neurons.

scholarly journals RasGRF1 regulates the hypothalamic–pituitary–adrenal axis specifically in early-adolescent female mice

2015 ◽  
Vol 227 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Belkis Gizem Uzturk ◽  
Shan-xue Jin ◽  
Beverly Rubin ◽  
Christopher Bartolome ◽  
Larry A Feig
Keyword(s):  
Psychiatric Disorders ◽  
Hpa Axis ◽  
Knockout Mice ◽  
Restraint Stress ◽  
Molecular Mechanisms ◽  
Early Adolescent ◽  
Adolescent Male ◽  
Adolescent Female ◽  
Nucleotide Exchange ◽  
Hypothalamic Pituitary Adrenal

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been implicated in the induction and prolongation of a variety of psychiatric disorders. As such, much effort has been made to understand the molecular mechanisms involved in its control. However, the vast majority of the studies on the HPA axis have used adult animals, and among these the majority has used males. Here we show that in knockout mice lacking the guanine nucleotide exchange factor, RasGRF1, habituation to 30 min/day of restraint stress is markedly accelerated, such that these mice do not display elevated corticosterone levels or enhanced locomotion after 7 days of stress exposure, like WT mice do. Strikingly, this phenotype is present in early-adolescent female RasGRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female, adult female or adult male counterparts. Moreover, not only is there a clear response to restraint stress in early-adolescent female RasGRF1 knockout mice, their response after one, three and five exposures is magnified approximately threefold compared to WT mice. These findings imply that distinct mechanisms exist to regulate the HPA axis in early-adolescent females that involves RasGRF1. A full understanding of how RasGRF1 controls the HPA axis response to stress may be required to design effective strategies to combat stress-associated psychiatric disorders initiated in young females.

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