Stimulation of endothelin B receptors in astrocytes induces cAMP response element-binding protein phosphorylation and c-fos expression via multiple mitogen-activated protein kinase signaling pathways.
The vasoconstrictor peptide endothelin (ET-1) exerts its physiological and pathological effects via activation of ET(A) and ET(B) receptor (ET-R) subtypes. In this study, we demonstrate that both ET-R subtypes are highly expressed in rat astrocytes in vivo, indicating that these cells are potential targets of the biological effects of ET-1 ... in the brain. In cultured cortical astrocytes, both ET-R subtypes are expressed, and selective stimulation of ET(B)-R with ET-1 induces phosphorylation of cAMP response element-binding protein (CREB). The signal transduction pathway activated by ET-1 includes the Rap1/B-Raf and the Ras/Raf-1 complexes, protein kinase C (PKC) together with extracellular signal-regulated kinases (ERK), and the ribosomal S6 kinase (RSK) isoforms RSK2 and RSK3, two kinases that lie immediately downstream of ERK and are able to phosphorylate CREB. Moreover, ET-1 activates the p38 mitogen-activated protein kinase (MAPK)-dependent, but not the c-jun N-terminal kinase (JNK)-dependent pathway. By using selective protein kinase inhibitors and expression of dominant-negative Rap1 protein, we also found that the Rap1/PKC/ERK-dependent pathway induces the phosphorylation of activating transcription factor-1, CREB, and Elk-1, whereas the p38MAPK-dependent pathway only causes CREB phosphorylation. ET-1-induced transcription of the immediate early gene c-fos requires the concomitant activation of both the PKC/ERK- and p38MAPK-dependent pathways, because inhibitors of either pathway block the ET-1-induced increase of c-fos mRNA. Our findings indicate that changes in the expression of cAMP response element-dependent immediate and delayed response genes could play a pivotal role in the physiological effects elicited by ET-1 in astrocytes.
Mesh Terms:
Activating Transcription Factor 1, Animals, Astrocytes, Cells, Cultured, Cyclic AMP Response Element-Binding Protein, DNA-Binding Proteins, Endothelin-1, Mitogen-Activated Protein Kinases, Phosphorylation, Protein Kinase C, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-raf, RNA, Messenger, Rats, Rats, Sprague-Dawley, Receptor, Endothelin A, Receptor, Endothelin B, Receptors, Endothelin, Signal Transduction, Transcription Factors, p38 Mitogen-Activated Protein Kinases, rap1 GTP-Binding Proteins
Activating Transcription Factor 1, Animals, Astrocytes, Cells, Cultured, Cyclic AMP Response Element-Binding Protein, DNA-Binding Proteins, Endothelin-1, Mitogen-Activated Protein Kinases, Phosphorylation, Protein Kinase C, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-raf, RNA, Messenger, Rats, Rats, Sprague-Dawley, Receptor, Endothelin A, Receptor, Endothelin B, Receptors, Endothelin, Signal Transduction, Transcription Factors, p38 Mitogen-Activated Protein Kinases, rap1 GTP-Binding Proteins
J Neurosci
Date: Nov. 15, 2001
PubMed ID: 11698596
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