Am. J. Respir. Cell Mol. Biol., Volume 20, Number 1, January, 1999 99-105

Endothelin-Stimulated ERK Activation in Airway Smooth-Muscle Cells Requires Calcium Influx and Raf Activation

Paul Vichi, Alyn Whelchel, Harm Knot, Mark Nelson, Walter Kolch, and James Posada

Department of Molecular Physiology and Biophysics and Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont; and The Institute of Clinical Molecular Biology and Tumorgenetics GSF, Munich, Germany

Endothelin (ET)-1 is a 21-amino-acid peptide that is a potent vasoconstrictor and mitogen. By binding to its G-protein coupled receptor, ET-1 stimulates the proliferation of airway smooth-muscle (ASM) cells, which may be involved in the pathogenesis of asthma. The ETB receptor stimulates activation of the extracellular regulated kinase 2 (ERK2), which is thought to be required for proliferation of ASM cells. Our findings reveal that ET rapidly activates Raf, and that dominant-negative Raf interferes with ET-induced ERK activation in ASM cells. Expression of the amino-terminal Ras-binding domain of Raf inhibited ET-induced ERK activation, suggesting that ET-stimulated Raf activation is a Ras-dependent process. Furthermore, ET-stimulated ERK and Raf activation in ASM cells require calcium influx; chelating extracellular calcium or preventing calcium influx through calcium channels inhibited ET-stimulated, but not phorbol ester-stimulated, ERK and Raf activation.

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