Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by ...Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit.The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment.Methods MK-801 was used to induce SZ in rats.Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats.The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment,respectively.Results The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats.Interestingly,among the upstream kinases of CREB,merely ERK1/2 was downregulated,while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats.The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133,and induced synaptic dysfunction in primary hippocampal neurons.Conversely,the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment.Conclusion These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment.The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.展开更多
In fasting mammals,the liver is the primary source of glucose production for maintenance of normoglycemia.In this setting,circulating peptide hormones and catecholamines cause hepatic glucose output by stimulating gly...In fasting mammals,the liver is the primary source of glucose production for maintenance of normoglycemia.In this setting,circulating peptide hormones and catecholamines cause hepatic glucose output by stimulating glycogen breakdown as well as de novo glucose production through gluconeogenesis.Fasting gluconeogenesis is regulated by a complex transcriptional cascade culminating in elevated expression of hepatic enzymes that promote gluconeogenesis and glucose export to the blood.The cAMP response element binding protein CREB and its co-activator CRTC2 play crucial roles in signal-dependent transcriptional regulation of gluconeogenesis.Recent work has identified a family of serine/threonine kinases,the salt inducible kinases(SIKs),which are subject to hormonal control and constrain gluconeogenic and lipogenic gene expression in liver.As normal regulation of gluconeogenesis and lipogenesis is disrupted in diabetic states,SIK kinases are poised to serve as therapeutic targets to modulate metabolic disturbances in diabetic patients.The purpose of this review is to 1)describe the identification of CRTCs CREB co-activators and their regulation by SIKs,2)discuss recent progress toward understanding regulation and function of SIKs in metabolism and 3)examine the potential clinical impact of therapeutics that target SIK kinase function.展开更多
基金supported in part by grants from National Natural Science Foundation of China(No.31929002,No.82201326 No.82071440 and No.92049107)Science,Technology and Innovation Commission of Shenzhen Municipality(No.JCYJ20210324141405014)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2020B1515120017)the Academic Frontier Youth Team Project to Xiao-chuan WANG from Huazhong University of Science and Technology.
文摘Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit.The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment.Methods MK-801 was used to induce SZ in rats.Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats.The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment,respectively.Results The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats.Interestingly,among the upstream kinases of CREB,merely ERK1/2 was downregulated,while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats.The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133,and induced synaptic dysfunction in primary hippocampal neurons.Conversely,the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment.Conclusion These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment.The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.
基金supported by grants from the Muscular Dystrophy Association(MDA 68640)the American Heart Association(AHA 09BGIA2261362)the University of Texas Health Science Center,Houston.
文摘In fasting mammals,the liver is the primary source of glucose production for maintenance of normoglycemia.In this setting,circulating peptide hormones and catecholamines cause hepatic glucose output by stimulating glycogen breakdown as well as de novo glucose production through gluconeogenesis.Fasting gluconeogenesis is regulated by a complex transcriptional cascade culminating in elevated expression of hepatic enzymes that promote gluconeogenesis and glucose export to the blood.The cAMP response element binding protein CREB and its co-activator CRTC2 play crucial roles in signal-dependent transcriptional regulation of gluconeogenesis.Recent work has identified a family of serine/threonine kinases,the salt inducible kinases(SIKs),which are subject to hormonal control and constrain gluconeogenic and lipogenic gene expression in liver.As normal regulation of gluconeogenesis and lipogenesis is disrupted in diabetic states,SIK kinases are poised to serve as therapeutic targets to modulate metabolic disturbances in diabetic patients.The purpose of this review is to 1)describe the identification of CRTCs CREB co-activators and their regulation by SIKs,2)discuss recent progress toward understanding regulation and function of SIKs in metabolism and 3)examine the potential clinical impact of therapeutics that target SIK kinase function.
