Pituitary Adenylate Cyclase-activating Polypeptide Type 1 Receptor (PAC1) Gene Is Suppressed by Transglutaminase 2 Activation

Abstract

Background:The expression of PAC1, a specific receptor for PACAP, is decreased in brain ischemia. Results: PAC1 expression was attenuated by inactivation of Sp1 through cross-linking by transglutaminase 2 (TG2) activated by ER stress. Conclusion: TG2 is involved in negative regulation of PAC1 gene expression. Significance: Suppression of PAC1 by TG2 might be involved in neuronal damage from brain ischemia.

Role of transglutaminase 2 in PAC1 receptor mediated protection against hypoxia-induced cell death and neurite outgrowth in differentiating N2a neuroblastoma cells

“…Although the PAC1 receptor is expressed in mitotic N2a cells (Leliévre et al, 1998;Miura et al, 2013) its functional expression in differentiating N2a cells has to our knowledge not been reported. Hence, this study has demonstrated for the first time functional expression of the PAC1 receptor in N2a cells induced to differentiate with retinoic acid.…”

“…Since some of these protein kinase pathways are associated with modulation of TG activity (PKA, PKC and ERK1/2) it is conceivable that the PAC1 receptor regulates TG activity. Since mouse N2a neuroblastoma cells express PAC1 receptors (Leliévre et al, 1998;Miura et al, 2013;) the primary aims of this study were (i) to determine whether the PAC1 receptor modulates TG2 activity in these cells and (ii) to assess the role of TG2 in PAC1 receptor-induced neuroprotection and neurite outgrowth The results obtained indicate that PAC1 receptor stimulation triggers TG2-mediated amine incorporation and protein cross-linking activity in differentiating N2a and SH-SY5Y cells. Furthermore, inhibition of TG2 attenuates PAC1 receptor-induced cytoprotection and neurite outgrowth.…”

Spinal astrocytic activation contributes to both induction and maintenance of pituitary adenylate cyclase-activating polypeptide type 1 receptor-induced long-lasting mechanical allodynia in mice

“…Sections were blocked in phosphate buffered saline containing 1% normal donkey serum (ImmunoBioScience, Mukilteo, WA, USA), 1% bovine serum albumin (Sigma), and 1% saponin (Sigma) for 1 h at room temperature, and incubated for three days at 4 C with the primary antibodies against PAC1 receptor (rabbit polyclonal, 1:1,000, nos. 93093, which was provided by Dr A Arimura), [42][43][44][45] neuronal nuclei (NeuN, mouse monoclonal, 1:200, Millipore), GFAP (mouse monoclonal, 1:500, Millipore), and ionized calcium binding adaptor molecule 1 (Iba1, goat polyclonal, 1:500, Abcam, Cambridge, UK). The sections were then incubated for 1 h at room temperature with Alexa Fluor 488-labeled donkey anti-rabbit IgG antibody (1: 1,000, Invitrogen, Carlsbad, CA), Alexa Fluor 594-labeled donkey anti-mouse IgG antibody (1:1,000, Invitrogen), and Alexa Fluor 594-labeled donkey anti-goat IgG antibody (1:1,000, Invitrogen).…”

Diverse Mechanisms of Sp1-Dependent Transcriptional Regulation Potentially Involved in the Adaptive Response of Cancer Cells to Oxygen-Deficient Conditions

“…Sp1 proteins can associate with each other on gene promoter regions, thereby synergistically activating target genes [ 39 ]. It has been reported that Sp1 can be cross-linked by increased transglutaminase expression in neuronal cell nuclei under conditions of brain ischemia [ 40 ]. Induction of this transglutaminase expression occurs through the unfolded protein response (UPR), a mechanism that is activated in severe hypoxic tumor microenvironments.…”