title: Mu- and kappa-opioids induce the differentiation of embryonic stem cells to neural progenitors.
abstract: Growth factors, hormones, and neurotransmitters have been implicated in the regulation of stem cell fate. Since various neural precursors express functional neurotransmitter receptors, which include G protein-coupled receptors, it is anticipated that they are involved in cell fate decisions. We detected mu-opioid receptor (MOR-1) and kappa-opioid receptor (KOR-1) expression and immunoreactivity in embryonic stem (ES) cells and in retinoic acid-induced ES cell-derived, nestin-positive, neural progenitors. Moreover, these G protein-coupled receptors are functional, since [D-Ala(2),MePhe(4),Gly-ol(5)]enkephalin, a MOR-selective agonist, and U69,593, a KOR-selective agonist, induce a sustained activation of extracellular signal-regulated kinase (ERK) signaling throughout a 24-h treatment period in undifferentiated, self-renewing ES cells. Both opioids promote limited proliferation of undifferentiated ES cells via the ERK/MAP kinase signaling pathway. Importantly, biochemical and immunofluorescence data suggest that [D-Ala(2),MePhe(4),Gly-ol(5)]enkephalin and U69,593 divert ES cells from self-renewal and coax the cells to differentiate. In retinoic acid-differentiated ES cells, opioid-induced signaling features a biphasic ERK activation profile and an opioid-induced, ERK-independent inhibition of proliferation in these neural progenitors. Collectively, the data suggest that opioids may have opposite effects on ES cell self-renewal and ES cell differentiation and that ERK activation is only required by the latter. Finally, opioid modulation of ERK activity may play an important role in ES cell fate decisions by directing the cells to specific lineages.
authors.affiliation: E. A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
authors.forename: Eunhae
authors.initials: E
authors.lastname: Kim
authors.forename: Amy L
authors.initials: AL
authors.lastname: Clark
authors.forename: Alexi
authors.initials: A
authors.lastname: Kiss
authors.forename: Jason W
authors.initials: JW
authors.lastname: Hahn
authors.forename: Robin
authors.initials: R
authors.lastname: Wesselschmidt
authors.forename: Carmine J
authors.initials: CJ
authors.lastname: Coscia
authors.forename: Mariana M
authors.initials: MM
authors.lastname: Belcheva
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D014212:Tretinoin; D020928:Mitogen-Activated Protein Kinases