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Agonist‐induced activation of histamine H3 receptor signals to extracellular signal‐regulated kinases 1 and 2 through PKC ‐, PLD ‐, and EGFR ‐dependent mechanisms
Author(s) -
Lai Xiangru,
Ye Lingyan,
Liao Yuan,
Jin Lili,
Ma Qiang,
Lu Bing,
Sun Yi,
Shi Ying,
Zhou Naiming
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13559
Subject(s) - histamine h3 receptor , microbiology and biotechnology , biology , staurosporine , agonist , kinase , mapk/erk pathway , neuroprotection , phosphorylation , protein kinase c , signal transduction , histamine , receptor , chemistry , pharmacology , biochemistry
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 ( ERK 1/2) remain to be elucidated. In this study, using HEK 293 cells stably expressing human H3R and mouse primary cortical neurons endogenously expressing mouse H3R, we found that the H3R‐mediated activation of ERK 1/2 was significantly blocked by both the pertussis toxin and the MEK 1/2 inhibitor U0126. Upon stimulation by H3R agonist histamine or imetit, H3R was shown to rapidly induce ERK 1/2 phosphorylation via PLC / PKC ‐, PLD s‐, and epidermal growth factor receptor ( EGFR ) transactivation‐dependent pathways. Furthermore, it was also indicated that while the βγ‐subunits play a key role in H3R‐activated ERK 1/2 phosphorylation, β‐arrestins were not required for ERK 1/2 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 UO 126 abolished these protective effects. This suggests a possible neuroprotective role of the H3R‐mediated ERK 1/2 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 ERK 1/2.Histamine H3 receptors are abundantly expressed in the brain and play important roles in various CNS physiological functions. However, the underlying mechanisms for H3R‐induced activation of extracellular signal‐regulated kinase (ERK)1/2 remain largely unknown. Here, we provide evidence that upon activation by an agonist, H3Rs trigger ERK1/2 activation via phospholipase C/protein kinase C (PLC/PKC)‐, phospholipase D (PLD)s‐, and matrix metallopeptidase/epidermal growth factor receptor (MMP/EGFR) transactivation‐dependent pathways. Moreover, we demonstrate that H3Rs exhibit a neuroprotective effect on the cultured mouse cortical neurons under hypoxia conditions through the ERK1/2 pathway.