title: Convergent effects of lithium and valproate on the expression of proteins associated with large dense core vesicles in NGF-differentiated PC12 cells.
abstract: Lithium and valproate are chemically unrelated compounds that are used to treat manic-depressive illness. Previously, we reported that lithium ions upregulate genes encoding proteins primarily associated with large dense core vesicles (LDCV) in nerve growth factor (NGF)-differentiated PC12 cells, but not in undifferentiated PC12 cells. Moreover, lithium did not alter the expression of proteins associated with small-clear, synaptic-like vesicles (SSV) in these cells. Based on these observations, we investigated whether valproate had actions similar to those of lithium in PC12 cells. Thus, undifferentiated or NGF-differentiated PC12 cells were exposed to lithium (1 mM) or valproate (1 mM) for 48 h. Extracts from these cells were submitted to semiquantitative Northern and Western analyses. In NGF-differentiated cells, both agents increased the expression of proteins associated with LDCV, the vesicular monoamine transporter 1 (VMAT1), and cysteine string protein (CSP). These same treatments did not alter the expression of proteins primarily associated with SSV, the vesicular acetylcholine transporter (VAChT), and synaptophysin (SY). Furthermore, neither drug affected the expression of these proteins in undifferentiated cells. Interestingly, secretion of (3)H-dopamine was increased in cells exhibiting the increase of VMAT1 and csp. Taken together, the convergent effects of these chemically diverse compounds suggest that altered dynamics of LDCV may play a vital role in the biochemical pathway, leading to the relief of the symptoms of manic depression.
authors.affiliation: Department of Molecular and Medical Pharmacology and Crump Institute for Molecular Imaging, UCLA, School of Medicine, Los Angeles, CA 90095-1770, USA.
authors.forename: Mara L
authors.initials: ML
authors.lastname: Cordeiro
authors.forename: Cameron B
authors.initials: CB
authors.lastname: Gundersen
authors.forename: Joy A
authors.initials: JA
authors.lastname: Umbach
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D050956:HSP40 Heat-Shock Proteins; D008094:Lithium / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D020932:Nerve Growth Factor / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D022142:Secretory Vesicles / Q000187:drug effects* / Q000378:metabolism; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014316:Tritium / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D050494:Vesicular Acetylcholine Transport Proteins; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D033921:Vesicular Transport Proteins
chemical_list: D000927:Anticonvulsants; D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D050956:HSP40 Heat-Shock Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C493451:Slc18a1 protein, rat; C493461:Slc18a3 protein, rat; D016708:Synaptophysin; D050494:Vesicular Acetylcholine Transport Proteins; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D033921:Vesicular Transport Proteins; C459407:Zwint protein, rat; C088460:cysteine string protein; D014316:Tritium; D014635:Valproic Acid; D011189:Potassium Chloride; D020932:Nerve Growth Factor; D008094:Lithium; D004298:Dopamine