Differential Activation of Mitogen‐Activated Protein Kinase Pathways in PC12 Cells by Closely Related α1‐Adrenergic Receptor Subtypes
: Coupling of the three known α1‐adrenergic receptor (α1‐AR) subtypes to mitogen‐activated protein kinase (MAPK) pathways were studied in stably transfected PC12 cells. Subclones stably expressing α1A‐, α1B‐, and α1D‐ARs under control of an inducible promoter, or at high and low receptor density, we...
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Veröffentlicht in: | Journal of neurochemistry 1999-06, Vol.72 (6), p.2388-2396 |
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Sprache: | eng |
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Zusammenfassung: | : Coupling of the three known α1‐adrenergic
receptor (α1‐AR) subtypes to mitogen‐activated
protein kinase (MAPK) pathways were studied in stably transfected PC12 cells.
Subclones stably expressing α1A‐,
α1B‐, and α1D‐ARs
under control of an inducible promoter, or at high and low receptor density,
were isolated and characterized. Radioligand binding showed similar ranges of
expression of each subtype. Norepinephrine (NE) increased inositol phosphate
formation and intracellular Ca2+ level in these cells in a manner
dependent on receptor density. However, α1A‐ARs
activated these second messenger responses more effectively than
α1B‐ARs, whereas α1D‐ARs were
least effective. NE stimulated activation of extracellular signal‐regulated
kinases (ERKs) in cells expressing all three α1‐AR
subtypes, although α1A‐ and
α1B‐ARs caused larger ERK activation than did
α1D‐ARs. Nerve growth factor (NGF) caused similar
levels of ERK activation in all subclones. NE also activated p38 MAPK in
α1A‐ and α1B‐ but not
α1D‐transfected cells and activated c‐Jun
NH2‐terminal kinase (JNK) only in α1A‐transfected
cells. NE, but not NGF, strongly stimulated tyrosine phosphorylation of a
70‐kDa protein only in α1A‐transfected PC12 cells. NE caused
neutrite outgrowth only in α1A‐expressing PC12 cells, but not
in α1B‐ or α1D‐transfected cells,
whereas NGF caused neurite outgrowth in all cells. These studies show that
α1A‐ARs activate all three MAPK pathways,
α1B‐ARs activate ERKs and p38 but not JNKs, and
α1D‐ARs only activate ERKs. Only the
α1A‐AR‐expressing cells differentiated in response to NE. The relationship of these responses to second messenger pathways activated by these subtypes is discussed. |
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ISSN: | 0022-3042 1471-4159 |
DOI: | 10.1046/j.1471-4159.1999.0722388.x |