Glucagon 信号在代谢调节中的作用
中文名称
通路描述
胰脏释放的胰高血糖素和胰岛素是肽类激素，正常情况下以互补方式稳定血糖浓度。当血糖水平升高时，胰岛素刺激血液中的葡萄糖摄取、葡萄糖分解（糖酵解）和葡萄糖储存为糖原。当血糖水平下降时，胰高血糖素释放刺激糖原分解和从头合成葡萄糖（糖异生），同时抑制糖酵解和糖原合成。在分子水平上，胰高血糖素与细胞外受体结合导致受体构象变化，使Gs和Gq亚基解离并激活。Gq的激活导致磷脂酶C激活、肌醇三磷酸产生及细胞内钙释放。Gs的激活导致腺苷酸环化酶激活、细胞内cAMP水平升高及蛋白激酶A（PKA）激活。活性PKA磷酸化糖原分解、糖原合成、糖异生和糖酵解的关键酶，从而调节其活性。这些信号转导事件及其下游后果如图所示（改编自Jiang和Zhang, 2003）。
英文描述
Regulation of NPAS4 gene transcription Transcription of the NPAS4 gene is positively regulated by neuronal stimulation-related increase in intracellular calcium levels (Lin et al. 2008; Zhang et al. 2009, Mellström et al. 2014; Lobos et al. 2021).
In the absence of neuronal activity induced calcium influx, KCNIP3 (DREAM) binds to the promoter of the NPAS4 gene and represses NPAS4 transcription (Mellström et al. 2014). In non-neuronal cells, REST protein represses transcription of the NPAS4 gene (Bersten et al. 2014). In neuronal cells, REST may have a dual effect on NPAS4 expression: acting as a positive regulator of NPAS4 transcription early upon neuronal excitation and as a negative regulator at later time points, allowing NPAS4 to return to basal levels (Prestigio et al. 2021). Binding of agonist activated glucocorticoid receptor NR3C1 (also known as GR) to evolutionarily conserved glucocorticoid response elements (GREs) upstream of the NPAS4 gene transcription start site is responsible for stress-induced repression of NPAS4 gene transcription (Furukawa Hibi et al. 2012). Chronic restraint stress as well as corticosterone injection also reduce Npas4 gene expression in the mouse hippocampus (Yun et al. 2010). Though mechanisms remain to be delineated, HDAC5 was reported by multiple studies to contribute to NPAS4 gene repression (Taniguchi et al. 2017, Hashikawa-Hobara et al. 2021; Lv et al. 2021; Rein et al. 2022). In addition, HDAC3 was reported as the NPAS4 gene repressor during neurodegeneration (Louis Sam Titus et al. 2019).
SRF (Serum response factor) stimulates NPAS4 gene transcription upon neuronal excitation (Kuzniewska et al. 2016, Lösing et al. 2017, Förstner and Knöll 2019). NPAS4 gene transcription is positively regulated by PI3K/AKT signaling (Ooe et al. 2009; Speckmann et al. 2016), and only partially dependent on ERK (MAPK) signaling (Blüthgen et al. 2017). NPAS4 may be one of the EGR1 target genes (Han et al. 2014). Neuronal activity stimulation may trigger the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including FOS, NPAS4, and EGR1, which may contribute to their transcriptional activation (Madabushi et al. 2015). NPAS4 appears to be a downstream target involved in amyloid precursor protein (APP)-dependent regulation of inhibitory synaptic transmission (Opsomer et al. 2020). TET1, a methylcytosine dioxygenase that catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promotes DNA demethylation is implicated in transcriptional activation of NPAS4 gene through demethylation of hypermethylated CpG dinucleotides in the NPAS4 gene promoter region (Rudenko et al. 2013). Transcriptional activation of the NPAS4 gene is associated with the appearance of H3K4me3 mark and 5hmC mark at the NPAS4 gene promoter (Webb et al. 2017).
In the absence of neuronal activity induced calcium influx, KCNIP3 (DREAM) binds to the promoter of the NPAS4 gene and represses NPAS4 transcription (Mellström et al. 2014). In non-neuronal cells, REST protein represses transcription of the NPAS4 gene (Bersten et al. 2014). In neuronal cells, REST may have a dual effect on NPAS4 expression: acting as a positive regulator of NPAS4 transcription early upon neuronal excitation and as a negative regulator at later time points, allowing NPAS4 to return to basal levels (Prestigio et al. 2021). Binding of agonist activated glucocorticoid receptor NR3C1 (also known as GR) to evolutionarily conserved glucocorticoid response elements (GREs) upstream of the NPAS4 gene transcription start site is responsible for stress-induced repression of NPAS4 gene transcription (Furukawa Hibi et al. 2012). Chronic restraint stress as well as corticosterone injection also reduce Npas4 gene expression in the mouse hippocampus (Yun et al. 2010). Though mechanisms remain to be delineated, HDAC5 was reported by multiple studies to contribute to NPAS4 gene repression (Taniguchi et al. 2017, Hashikawa-Hobara et al. 2021; Lv et al. 2021; Rein et al. 2022). In addition, HDAC3 was reported as the NPAS4 gene repressor during neurodegeneration (Louis Sam Titus et al. 2019).
SRF (Serum response factor) stimulates NPAS4 gene transcription upon neuronal excitation (Kuzniewska et al. 2016, Lösing et al. 2017, Förstner and Knöll 2019). NPAS4 gene transcription is positively regulated by PI3K/AKT signaling (Ooe et al. 2009; Speckmann et al. 2016), and only partially dependent on ERK (MAPK) signaling (Blüthgen et al. 2017). NPAS4 may be one of the EGR1 target genes (Han et al. 2014). Neuronal activity stimulation may trigger the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including FOS, NPAS4, and EGR1, which may contribute to their transcriptional activation (Madabushi et al. 2015). NPAS4 appears to be a downstream target involved in amyloid precursor protein (APP)-dependent regulation of inhibitory synaptic transmission (Opsomer et al. 2020). TET1, a methylcytosine dioxygenase that catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promotes DNA demethylation is implicated in transcriptional activation of NPAS4 gene through demethylation of hypermethylated CpG dinucleotides in the NPAS4 gene promoter region (Rudenko et al. 2013). Transcriptional activation of the NPAS4 gene is associated with the appearance of H3K4me3 mark and 5hmC mark at the NPAS4 gene promoter (Webb et al. 2017).
所含基因
4 个基因