Limits...
Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression.

Papadopoulou A, Siamatras T, Delgado-Morales R, Amin ND, Shukla V, Zheng YL, Pant HC, Almeida OF, Kino T - Transl Psychiatry (2015)

Bottom Line: Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation.In mice, acute immobilized stress (AS) caused a biphasic effect on CDK5 activity, initially reducing but increasing afterwards in prefrontal cortex (PFC) and hippocampus (HIPPO), whereas chronic unpredictable stress (CS) strongly increased it in these brain areas, indicating that AS and CS differentially regulate this kinase activity in a brain region-specific fashion.GR phosphorylation contemporaneously followed the observed changes of CDK5 activity after AS, thus CDK5 may in part alter GR phosphorylation upon this stress.

View Article: PubMed Central - PubMed

Affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

ABSTRACT
Stress activates the hypothalamic-pituitary-adrenal axis, which in turn increases circulating glucocorticoid concentrations and stimulates the glucocorticoid receptor (GR). Chronically elevated glucocorticoids by repetitive exposure to stress are implicated in major depression and anxiety disorders. Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation. We examined potential contribution of CDK5 to stress response and pathophysiology of major depression. In mice, acute immobilized stress (AS) caused a biphasic effect on CDK5 activity, initially reducing but increasing afterwards in prefrontal cortex (PFC) and hippocampus (HIPPO), whereas chronic unpredictable stress (CS) strongly increased it in these brain areas, indicating that AS and CS differentially regulate this kinase activity in a brain region-specific fashion. GR phosphorylation contemporaneously followed the observed changes of CDK5 activity after AS, thus CDK5 may in part alter GR phosphorylation upon this stress. In the postmortem brains of subjects with major depression, CDK5 activity was elevated in Brodmann's area 25, but not in entire PFC and HIPPO. Messenger RNA expression of glucocorticoid-regulated/stress-related genes showed distinct expression profiles in several brain areas of these stressed mice or depressive subjects in which CDK5-mediated changes in GR phosphorylation may have some regulatory roles. Taken together, these results indicate that CDK5 is an integral component of stress response and major depression with regulatory means specific to different stressors, brain areas and diseases in part through changing phosphorylation of GR.

No MeSH data available.


Related in: MedlinePlus

Acute stress, corticosterone injection and chronic stress differentially regulate phosphorylation of GR at serine 220 in mouse PFC and HIPPO. Mice were either immobilized in a 50 ml Falcon tube for 1 h (acute stress), injected with corticosterone (CORT, 20 mg kg−1) intraperitoneally (a and b) or treated with chronic unpredictable stress for 28 days (c) and their PFC and HIPPO were obtained at the time points indicated. The GR phosphorylated at serine 220 (P-GR) was examined with western blots using a specific antibody for this phosphorylated GR and relative P-GR levels were calculated by correcting band density of P-GR with that of total GR. Bars represent mean±s.e. values of relative P-GR levels. *P<0.05; **P<0.01; n.s., not significant, compared with the conditions indicated. GR, glucocorticoid receptor; HIPPO, hippocampus; PFC, prefrontal cortex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4490283&req=5

fig3: Acute stress, corticosterone injection and chronic stress differentially regulate phosphorylation of GR at serine 220 in mouse PFC and HIPPO. Mice were either immobilized in a 50 ml Falcon tube for 1 h (acute stress), injected with corticosterone (CORT, 20 mg kg−1) intraperitoneally (a and b) or treated with chronic unpredictable stress for 28 days (c) and their PFC and HIPPO were obtained at the time points indicated. The GR phosphorylated at serine 220 (P-GR) was examined with western blots using a specific antibody for this phosphorylated GR and relative P-GR levels were calculated by correcting band density of P-GR with that of total GR. Bars represent mean±s.e. values of relative P-GR levels. *P<0.05; **P<0.01; n.s., not significant, compared with the conditions indicated. GR, glucocorticoid receptor; HIPPO, hippocampus; PFC, prefrontal cortex.

Mentions: We previously reported that CDK5 modulates GR-induced transcriptional activity through phosphorylation of this receptor.24 Thus, we examined the effect of acute or chronic stress on the phosphorylation of GR in PFC and HIPPO, using western blots with the antibody specifically reacting to the GR phosphorylated at serine 220, the residue known to be phosphorylated by CDK5.24, 33 AS increased GR phosphorylation 24 h after the exposure in PFC, while it suppressed GR phosphorylation after 1 h and increased after 3 h in HIPPO (Figures 3a and b). CORT injection increased GR phosphorylation after 1 h in PFC, while the injection increased it after 1 h and 3 h in HIPPO (Figures 3a and b), consistent with a well-known fact that GR is phosphorylated just after binding to ligand.45 These results indicate that the elevation of CDK5 activity by AS, respectively, observed after 24 h and 3 h in PFC and HIPPO may account for the elevation of GR phosphorylation in these areas. AS reduced CDK5 activity at 1 h time point in PFC and HIPPO, whereas CORT injection increased the phosphorylation at the same time point. Thus, mixture of these opposing activities observed upon AS might have caused the mild changes in the GR phosphorylation at early time points upon exposure to this stress. In contrast to AS, CS reduced GR phosphorylation in PFC but not in HIPPO (Figure 3c), while CDK5 activity was elevated in these brain areas (Figure 2b). Thus, unknown mechanisms appear to be functional in the regulation of GR phosphorylation following exposure to CS.


Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression.

Papadopoulou A, Siamatras T, Delgado-Morales R, Amin ND, Shukla V, Zheng YL, Pant HC, Almeida OF, Kino T - Transl Psychiatry (2015)

Acute stress, corticosterone injection and chronic stress differentially regulate phosphorylation of GR at serine 220 in mouse PFC and HIPPO. Mice were either immobilized in a 50 ml Falcon tube for 1 h (acute stress), injected with corticosterone (CORT, 20 mg kg−1) intraperitoneally (a and b) or treated with chronic unpredictable stress for 28 days (c) and their PFC and HIPPO were obtained at the time points indicated. The GR phosphorylated at serine 220 (P-GR) was examined with western blots using a specific antibody for this phosphorylated GR and relative P-GR levels were calculated by correcting band density of P-GR with that of total GR. Bars represent mean±s.e. values of relative P-GR levels. *P<0.05; **P<0.01; n.s., not significant, compared with the conditions indicated. GR, glucocorticoid receptor; HIPPO, hippocampus; PFC, prefrontal cortex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490283&req=5

fig3: Acute stress, corticosterone injection and chronic stress differentially regulate phosphorylation of GR at serine 220 in mouse PFC and HIPPO. Mice were either immobilized in a 50 ml Falcon tube for 1 h (acute stress), injected with corticosterone (CORT, 20 mg kg−1) intraperitoneally (a and b) or treated with chronic unpredictable stress for 28 days (c) and their PFC and HIPPO were obtained at the time points indicated. The GR phosphorylated at serine 220 (P-GR) was examined with western blots using a specific antibody for this phosphorylated GR and relative P-GR levels were calculated by correcting band density of P-GR with that of total GR. Bars represent mean±s.e. values of relative P-GR levels. *P<0.05; **P<0.01; n.s., not significant, compared with the conditions indicated. GR, glucocorticoid receptor; HIPPO, hippocampus; PFC, prefrontal cortex.
Mentions: We previously reported that CDK5 modulates GR-induced transcriptional activity through phosphorylation of this receptor.24 Thus, we examined the effect of acute or chronic stress on the phosphorylation of GR in PFC and HIPPO, using western blots with the antibody specifically reacting to the GR phosphorylated at serine 220, the residue known to be phosphorylated by CDK5.24, 33 AS increased GR phosphorylation 24 h after the exposure in PFC, while it suppressed GR phosphorylation after 1 h and increased after 3 h in HIPPO (Figures 3a and b). CORT injection increased GR phosphorylation after 1 h in PFC, while the injection increased it after 1 h and 3 h in HIPPO (Figures 3a and b), consistent with a well-known fact that GR is phosphorylated just after binding to ligand.45 These results indicate that the elevation of CDK5 activity by AS, respectively, observed after 24 h and 3 h in PFC and HIPPO may account for the elevation of GR phosphorylation in these areas. AS reduced CDK5 activity at 1 h time point in PFC and HIPPO, whereas CORT injection increased the phosphorylation at the same time point. Thus, mixture of these opposing activities observed upon AS might have caused the mild changes in the GR phosphorylation at early time points upon exposure to this stress. In contrast to AS, CS reduced GR phosphorylation in PFC but not in HIPPO (Figure 3c), while CDK5 activity was elevated in these brain areas (Figure 2b). Thus, unknown mechanisms appear to be functional in the regulation of GR phosphorylation following exposure to CS.

Bottom Line: Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation.In mice, acute immobilized stress (AS) caused a biphasic effect on CDK5 activity, initially reducing but increasing afterwards in prefrontal cortex (PFC) and hippocampus (HIPPO), whereas chronic unpredictable stress (CS) strongly increased it in these brain areas, indicating that AS and CS differentially regulate this kinase activity in a brain region-specific fashion.GR phosphorylation contemporaneously followed the observed changes of CDK5 activity after AS, thus CDK5 may in part alter GR phosphorylation upon this stress.

View Article: PubMed Central - PubMed

Affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

ABSTRACT
Stress activates the hypothalamic-pituitary-adrenal axis, which in turn increases circulating glucocorticoid concentrations and stimulates the glucocorticoid receptor (GR). Chronically elevated glucocorticoids by repetitive exposure to stress are implicated in major depression and anxiety disorders. Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation. We examined potential contribution of CDK5 to stress response and pathophysiology of major depression. In mice, acute immobilized stress (AS) caused a biphasic effect on CDK5 activity, initially reducing but increasing afterwards in prefrontal cortex (PFC) and hippocampus (HIPPO), whereas chronic unpredictable stress (CS) strongly increased it in these brain areas, indicating that AS and CS differentially regulate this kinase activity in a brain region-specific fashion. GR phosphorylation contemporaneously followed the observed changes of CDK5 activity after AS, thus CDK5 may in part alter GR phosphorylation upon this stress. In the postmortem brains of subjects with major depression, CDK5 activity was elevated in Brodmann's area 25, but not in entire PFC and HIPPO. Messenger RNA expression of glucocorticoid-regulated/stress-related genes showed distinct expression profiles in several brain areas of these stressed mice or depressive subjects in which CDK5-mediated changes in GR phosphorylation may have some regulatory roles. Taken together, these results indicate that CDK5 is an integral component of stress response and major depression with regulatory means specific to different stressors, brain areas and diseases in part through changing phosphorylation of GR.

No MeSH data available.


Related in: MedlinePlus