Agonist‐induced activation of histamine H3 receptor signals to extracellular signal‐regulated kinases 1 and 2 through PKC‐, PLD‐, and EGFR‐dependent mechanisms

Abstract

The histamine H3 receptor (H3R), abundantly expressed in the central and the peripheral nervous system, has been recognized as a promising target for the treatment of various important CNS diseases including narcolepsy, Alzheimer's disease, and attention deficit hyperactivity disorder. The H3R acts via G i/o -proteins to inhibit adenylate cyclase activity and modulate MAPK activity. However, the underlying molecular mechanisms for H3R mediation of the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) remain to be elucidated. In this study, using HEK293 cells stably expressing human H3R and mouse primary cortical neurons endogenously expressing mouse H3R, we found that the H3R-mediated activation of ERK1/2 was significantly blocked by both the pertussis toxin and the MEK1/2 inhibitor U0126. Upon stimulation by H3R agonist histamine or imetit, H3R was shown to rapidly induce ERK1/2 phosphorylation via PLC/ PKC-, PLDs-, and epidermal growth factor receptor (EGFR) transactivation-dependent pathways. Furthermore, it was also indicated that while the bc-subunits play a key role in H3R-activated ERK1/2 phosphorylation, b-arrestins were not required for ERK1/2 activation. In addition, when the cultured mouse cortical neurons were exposed to oxygen and glucose deprivation conditions (OGD), imetit exhibited neuroprotective properties through the H3R. Treatment of cells with the inhibitor UO126 abolished these protective effects. This suggests a possible neuroprotective role of the H3R-mediated ERK1/2 pathway under hypoxia conditions. These observations may provide new insights into the pharmacological effects and the physiological functions modulated by the H3R-mediated activation of ERK1/2.

GABABR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells

“…The EGFR family has received much attention in pharmacological research due to their strong association with malignant proliferation (Gallick et al, 2012). In addition to direct activation by specific ligands, EGFR family members could also be transactivated by a variety of GPCR agonists (Daub et al, 1996;Zhou et al, 2012;Cattaneo et al, 2014;Muñoz-Moreno et al, 2014;Lai et al, 2016;Wang, 2016). In this study, we demonstrated for the first time that specific activation of GABA B R, a neurotransmitter receptor belonging to the GPCR family, selectively induced EGFR transactivation in PC-3 cells.…”

“…GPCR-induced EGFR transactivation can activate ERK1/2 signaling cascades (Xiao et al, 2003;Zhou et al, 2012;George et al, 2013;Lai et al, 2016). To examine whether EGFR transactivation by GABA B R induced ERK1/2 activation, PC-3 cells were treated with baclofen or GABA for various period of Fig.…”

ERK and p38 Upregulation versus Bcl-6 Downregulation in Rat Kidney Epithelial Cells Exposed to Prolonged Hypoxia

“…Our work and those of others have suggested that PKC, PKA, and Bcl-2 are directly or indirectly involved in MAPK signaling in hypoxic injury or protection against hypoxic injury. 27 , 66 – 69 For example, Bcl-2 confers protection against nuclear mitochondrial impairment under oxidative stress in pheochromocytoma (PC-12) cells, and a reduction in Bcl-2 expression leads to cell injury. 70 However, we did not find any appreciable change in the kidney epithelial cells, even after 72 h of hypoxia, which was different from what we saw in hypoxic neurons.…”

Cyclooxygenase-2 induced β1-integrin expression in NSCLC and promoted cell invasion via the EP1/MAPK/E2F-1/FoxC2 signal pathway

“…In the present study, FoxC2 siRNA suppressed β1-integrin expression and EP1R-mediated cell migration in NSCLC cells; the EP1 agonist improved FoxC2 expression; while Rottlerin suppressed EP1R-mediated FoxC2 expression significantly; ChIP assay identified that EP1 agonist treatment increased FoxC2 binding to β1-integrin promoter. MAPKs are involved in PKC downstream signalling pathway 32 33 . We found that the EP1 agonist improved both Erk1/2 and p38 phosphorylation in A549 cells, and that MEK1/2 and p38 inhibitors, suppressed EP1R-mediated β1-integrin upregulation.…”