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 and corticosterone injection differentially regulate CDK5 activity and protein expression in mouse PFC and HIPPO. Mice were immobilized in a 50 ml Falcon tube for 1 h or injected intraperitoneally with corticosterone (CORT, 20 mg kg−1) and were killed at 0, 1, 3 and 24 h after the treatment. CDK5 activity (a and b) and protein expression (c and d) were examined respectively with the CDK kinase assay and with the western blot using anti-CDK5 antibody. Bars represent mean±s.e. values of fold kinase activity against baseline (the condition at time 0 for AS, and the condition at 1 h in the absence of CORT for CORT injection) and the protein levels of CDK5. *P<0.05, **P<0.01, compared with the conditions indicated. HIPPO, hippocampus; PFC, prefrontal cortex.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Acute stress and corticosterone injection differentially regulate CDK5 activity and protein expression in mouse PFC and HIPPO. Mice were immobilized in a 50 ml Falcon tube for 1 h or injected intraperitoneally with corticosterone (CORT, 20 mg kg−1) and were killed at 0, 1, 3 and 24 h after the treatment. CDK5 activity (a and b) and protein expression (c and d) were examined respectively with the CDK kinase assay and with the western blot using anti-CDK5 antibody. Bars represent mean±s.e. values of fold kinase activity against baseline (the condition at time 0 for AS, and the condition at 1 h in the absence of CORT for CORT injection) and the protein levels of CDK5. *P<0.05, **P<0.01, compared with the conditions indicated. HIPPO, hippocampus; PFC, prefrontal cortex.

Mentions: Both in PFC and in HIPPO, AS developed a biphasic effect on the CDK5 activity: it suppressed the CDK5 activity 1 h after the exposure, while it reciprocally increased after 24 h in PFC (Figure 1a) and after 3 h in HIPPO (Figure 1b). CORT injection also suppressed the CDK5 activity 1 h after the injection in PFC (Figure 1a) and increased it after 3 h in HIPPO (Figure 1b), indicating a potential cause–effect relationship between elevated CORT secretion and the early changes in CDK5 activity observed upon exposure to AS.


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 and corticosterone injection differentially regulate CDK5 activity and protein expression in mouse PFC and HIPPO. Mice were immobilized in a 50 ml Falcon tube for 1 h or injected intraperitoneally with corticosterone (CORT, 20 mg kg−1) and were killed at 0, 1, 3 and 24 h after the treatment. CDK5 activity (a and b) and protein expression (c and d) were examined respectively with the CDK kinase assay and with the western blot using anti-CDK5 antibody. Bars represent mean±s.e. values of fold kinase activity against baseline (the condition at time 0 for AS, and the condition at 1 h in the absence of CORT for CORT injection) and the protein levels of CDK5. *P<0.05, **P<0.01, compared with the conditions indicated. HIPPO, hippocampus; PFC, prefrontal cortex.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Acute stress and corticosterone injection differentially regulate CDK5 activity and protein expression in mouse PFC and HIPPO. Mice were immobilized in a 50 ml Falcon tube for 1 h or injected intraperitoneally with corticosterone (CORT, 20 mg kg−1) and were killed at 0, 1, 3 and 24 h after the treatment. CDK5 activity (a and b) and protein expression (c and d) were examined respectively with the CDK kinase assay and with the western blot using anti-CDK5 antibody. Bars represent mean±s.e. values of fold kinase activity against baseline (the condition at time 0 for AS, and the condition at 1 h in the absence of CORT for CORT injection) and the protein levels of CDK5. *P<0.05, **P<0.01, compared with the conditions indicated. HIPPO, hippocampus; PFC, prefrontal cortex.
Mentions: Both in PFC and in HIPPO, AS developed a biphasic effect on the CDK5 activity: it suppressed the CDK5 activity 1 h after the exposure, while it reciprocally increased after 24 h in PFC (Figure 1a) and after 3 h in HIPPO (Figure 1b). CORT injection also suppressed the CDK5 activity 1 h after the injection in PFC (Figure 1a) and increased it after 3 h in HIPPO (Figure 1b), indicating a potential cause–effect relationship between elevated CORT secretion and the early changes in CDK5 activity observed upon exposure to AS.

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