Astrocytic transactivation by alpha2A-adrenergic and 5-HT2B serotonergic signaling.
EGF receptor transactivation has been known for more than ten years. It is a signal pathway in which a G-protein-coupled receptor (GPCR) signal leads to release of a growth factor, which in turn activates the EGF receptor-tyrosine kinase in the same or adjacent cells. Astrocytes express a number of GPCRs and play key roles in brain function. Astrocytic transactivation is of special interest, since its autocrine effect may regulate gene expression and alter cell functions in the cells themselves and its paracrine effect may provide additional opportunities for cross-talk between astrocytes and their neighbors, such as neurons. The signal pathways of EGF transactivation are complicated. This does not only apply to the pathways leading to shedding of growth factor(s), but also to the downstream signal pathways of the EGF receptor, i.e., MAPK and PI3K. The latter may vary according to the type of growth factor released, the sites of tyrosine phosphorylation on the EGF receptor, and the duration of the phosphorylation. Using primary cell cultures we have found that dexmedetomidine, a specific alpha(2)-adrenergic receptor, induced shedding of HB-EGF from astrocytes, which in turn transactivated EGF receptors and stimulated astrocytic c-Fos and FosB expression. At the same time released HB-EGF protected neurons from injury caused by H(2)O(2). We have also confirmed dexmedetomidine transactivation in the brain in vivo. EGF transactivation by 5-HT(2B) receptor stimulation was responsible for up-regulation of cPLA(2) in astrocytes by fluoxetine, an antidepressant and inhibitor of the serotonin transporter, which also is a specific 5-HT(2B) agonist.
Peng
Liang
L
Department of Clinical Pharmacology, China Medical University, China Medical University, Heping District, Shenyang, PR China. hkkid08@yahoo.com
Li
Baoman
B
Du
Ting
T
Kong
Ebenezer K C
EK
Hu
Xiaoling
X
Zhang
Shiquen
S
Shan
Xiaolei
X
Zhang
Meixia
M
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D020927:Dexmedetomidine / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D008024:Ligands; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
C547768:ADRA2A protein, human; D000316:Adrenergic alpha-Agonists; D008024:Ligands; D044403:Receptor, Serotonin, 5-HT2B; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine; D066246:ErbB Receptors