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The Journal of Neuroscience, November 15, 2001, 21(22):8842-8853

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

Sergio Schinelli^{1, 2}, Patrizia Zanassi², Mayra Paolillo², Hang Wang¹, Antonio Feliciello³, and Vittorio Gallo¹

¹ Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, ² Dipartimento di Farmacologia Sperimentale ed Applicata, Facoltá di Farmacia dell'Universitá di Pavia, Pavia 27100, Italy, and ³ Dipartimento di Biologia e Patologia Cellulare e Molecolare, Consiglio Nazionale delle Ricerche, Napoli 80131, Italy

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.

Key words: glia; Rap1; Elk-1; protein kinase C; Raf kinase; ribosomal S6 kinase

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21228842-12$05.00/0

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