alpha(1)-adrenoceptor subtypes differentially couple to growth promotion and inhibition in Chinese hamster ovary cells.
We have compared the coupling of human alpha(1A)-, alpha(1B)-, and alpha(1D)-adrenoceptors (expressed at approximately 2000 fmol/mg protein in Chinese hamster ovary cells) to cellular growth promotion (as assessed by [(3)H]thymidine incorporation) and related signaling mechanisms. Maximum elevation of intracellular Ca(2+) by the three subtypes occurred with the rank order alpha(1A) (1691 nM) > alpha(1D) (1215 nM) > alpha(1B) (360 nM). In contrast, activation of the ERK, JNK, and p38 forms of mitogen-activated protein kinases occurred with the rank order alpha(1D) > alpha(1A) > alpha(1B). alpha(1A)-Adrenoceptor stimulation inhibited basal and growth factor-stimulated [(3)H]thymidine incorporation by 74%, and this was mitigated by p38 inhibition. In contrast, alpha(1D)-adrenoceptor stimulation enhanced cellular growth by 136%, and this was blocked by two distinct inhibitors of ERK activation. We conclude that within a given cell type alpha(1)-adrenoceptor subtypes can have opposite effects on cellular growth, although their proximal signal transduction displays only quantitative differences.
Keffel
S
S
Department of Medicine, University of Essen, Germany.
Alexandrov
A
A
Goepel
M
M
Michel
M C
MC
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000145:classification* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium