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
Hauptverfasser: Zhong, Hongying, Minneman, Kenneth P.
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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.
ISSN:0022-3042
1471-4159
DOI:10.1046/j.1471-4159.1999.0722388.x