Balance between cAMP and Ca²⁺ signals regulates expression levels of pituitary adenylate cyclase‐activating polypeptide gene in neurons

Abstract

Mice lacking the gene encoding pituitary adenylate cyclase-activating polypeptide (PACAP) or its specific receptor, PAC1, show abnormal behaviors related to schizophrenia. However, the regulation of PACAP expression in neurons remains unclear. Here, we report that Pacap mRNA levels are regulated transcriptionally and post-transcriptionally by cAMP and Ca 2+ signals in cultured rat cortical cells. Pacap mRNA levels decreased proportionately with the intensity of cAMP signaling, and this decrease was accelerated by N-methyl-D-aspartate (NMDA) receptor blockade, suggesting that cAMP signaling enhances the degradation of Pacap mRNA, whereas NMDA receptor-mediated signals inhibit its degradation. However, depolarization (which produced a robust increase in Ca 2+ signals) together with cAMP signaling resulted in a synergistic induction of Pacap mRNA through calcineurin and its substrate, cAMP-response element-binding protein (CREB)-regulated transcription coactivator 1. These results strongly support the concept that while cAMP signaling can accelerate the degradation of Pacap mRNA, it can also synergistically enhance Ca 2+ signaling-induced transcriptional activation of Pacap. Taken together, our findings suggest that a balance between Ca 2+ and cAMP signals regulates PACAP levels in neurons and that a perturbation of this balance may result in psychiatric disorders, such as schizophrenia.

Kynurenic Acid Inhibits the Electrical Stimulation Induced Elevated Pituitary Adenylate Cyclase-Activating Polypeptide Expression in the TNC

“…To reveal the long-term effects of PACAP in the migraine is needs further investigations. Our results are consistent with previous studies, which reported that the main mediator of PACAP gene expression is intracellular calcium homeostasis ( 19 ). Indeed, besides the action of voltage-dependent calcium channels, the main inducer of PACAP gene expression is calcium influx through the NMDARs.…”

“… Regulation of PACAP gene expression [based on Fukuchi et al ( 19 ), genes to cells]. Abbreviations: AC, adenylate cylase; ATP, adenosine monophosphate; CaM, calmodulin; cAMP, cyclic adenosine monophosphate; CN, calcineurin; CREB, cAMP response element binding protein; CRTC1, CN/Cre binding protein; GPCR, G protein-coupled receptor; Gs, stimulatory G protein; KYNA, kynurenic acid; MAPK, mitogen-activated protein kinase; NMDAR, N -methyl- d -aspartate glutamate receptor; PKC, protein kinase C; PACAP, pituitary adenylate cyclase-activating polypeptide.…”

“…To date, only a few studies have provided evidence for an association between PACAP and the NMDAR. Calcium influx through the NMDAR is an important mediator of PACAP expression, inducing gene transcription via the mitogen-activated protein kinase signaling cascade ( 19 ). PACAP has been demonstrated to enhance the functional coupling of neuronal nitrogen-monoxide synthase and the NMDAR in models of both inflammatory and neuropathic pain ( 20 ).…”

PACAP deficiency as a model of aging

“…The action on the signaling pathways and thus, the physiological or pharmacological effects depend on the expressed receptors, tissue/cell types, and other factors present in the environment (Vaudry et al 2009). The expression of PACAP and the activation of PAC1/PACAP signaling also depend on a variety of factors, including developmental stage (Basille et al 2000), balance between signaling pathways (Fukuchi et al 2016), environmental factors (Horvath et al 2015), physiological conditions (Kiss et al 2007;Nemeth et al 2006;Rudecki and Gray 2016), daily rhythm (Jozsa et al 2001;Somogyvari-Vigh et al 2002), and the presence of harmful stimuli (Giunta et al 2012;Lam et al 2012;Pettersson et al 2014;Somogyvari-Vigh et al 2002;Szakaly et al 2010) and pathological conditions (Ergang et al 2015;Feher et al 2018;Han et al 2014aHan et al , 2014bHelyes et al 2015;Sarszegi et al 2018). PACAP's actions are very diverse, among others, it plays important roles during the development of the nervous system and several peripheral organs (Fulop et al 2018a;Watanabe et al 2016), influences anxiety, stress coping and addictionrelated behaviors (Iemolo et al 2016;King et al 2017;Kormos et al 2016;Mai et al 2018;Miles et al 2018), cognitive functions (Han et al 2014a(Han et al , 2014b, feeding (Sekar et al 2017), thermoregulation (Barrett et al 2017;Garami et al 2016), endocrine functions (Egri et al 2016;…”

Suxiao Jiuxin Pill protects cardiomyocytes against mitochondrial injury and alters gene expression during ischemic injury

“…Adcys are activated or inhibited by guanine nucleotide binding proteins (G proteins), which are coupled to membrane receptors that respond to hormonal stimulations, among others ( 35 ). cAMP, as a second messenger, serves as a regulatory signal through its interactions with cAMP-binding proteins, including protein kinase A, ion channels, transcription factors and enzymes ( 36 , 37 ).…”