title: Stimulation of α1a adrenergic receptors induces cellular proliferation or antiproliferative hypertrophy dependent solely on agonist concentration.
abstract: Stimulation of α1aAdrenergic Receptors (ARs) is known to have anti-proliferative and hypertrophic effects; however, some studies also suggests this receptor can increase cell proliferation. Surprisingly, we find the α1aAR expressed in rat-1 fibroblasts can produce either phenotype, depending exclusively on agonist concentration. Stimulation of the α1aAR by high dose phenylephrine (>10(-7) M) induces an antiproliferative, hypertrophic response accompanied by robust and extended p38 activation. Inhibition of p38 with SB203580 prevented the antiproliferative response, while inhibition of Erk or Jnk had no effect. In stark contrast, stimulation of the α1aAR with low dose phenylephrine (∼10(-8) M) induced an Erk-dependent increase in cellular proliferation. Agonist-induced Erk phosphorylation was preceded by rapid FGFR and EGFR transactivation; however, only EGFR inhibition blocked Erk activation and proliferation. The general matrix metalloprotease inhibitor, GM6001, blocked agonist induced Erk activation within seconds, strongly suggesting EGFR activation involved extracellular triple membrane pass signaling. Erk activation required little Ca(2+) release and was blocked by PLCβ or PKC inhibition but not by intracellular Ca(2+) chelation, suggesting Ca(2+) independent activation of novel PKC isoforms. In contrast, Ca(2+) release was essential for PI3K/Akt activation, which was acutely maximal at non-proliferative doses of agonist. Remarkably, our data suggests EGFR transactivation leading to Erk induced proliferation has the lowest activation threshold of any α1aAR response. The ability of α1aARs to induce proliferation are discussed in light of evidence suggesting antagonistic growth responses reflect native α1aAR function.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Beilei
authors.initials: B
authors.lastname: Lei
authors.forename: Debra A
authors.initials: DA
authors.lastname: Schwinn
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Morris
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D007093:Imidazoles / Q000494:pharmacology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*
chemical_list: D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D011725:Pyridines; D018340:Receptors, Adrenergic, alpha-1; D011494:Protein Kinases; C093642:SB 203580