Abstract
Lithium perturbs intracellular signal transduction pathways used by neurotransmitters, suggesting that changes in receptor signalling may underlie its actions in the treatment of manic depressive illness. Little attention, however, has been directed toward possible additional actions at the level of specific gene expression, particularly of genes encoding neurotransmitters or neuromodulators. In PC12 pheochromocytoma cells, lithium dramatically potentiates increases in intracellular levels of the neuropeptide neurotensin and the mRNA encoding it, caused by combinations of nerve growth factor, dexamethasone, and the adenylate cyclase activator, forskolin. This result demonstrates that lithium can profoundly influence the expression of a specific neuropeptide gene in a previously unanticipated manner and suggests that changes in gene expression might be involved in its therapeutic activity.
Highlights
From the Department of Molecular Genetics and Microbiology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, §Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts 021 11,and VDepartment of Medicine, Royal Postgraduate Medical School,Hammersmith Hospital, expression by the PC12 cell line may reflect expression in uiuo
We report here clase activator, forskolin.Thisresultdemonstrates the unexpected observation that lithium dramatically potenthat lithium can profoundly influence the expression tiates NT/N gene expression in PC12 cells
Of a specific neuropeptide gene in a previously unanticipatedmannerand suggests that changes in gene expression might beinvolved in its therapeutic activ- Materials-Restriction and other enzymes were from Boehringer ity
Summary
Expression might beinvolved in its therapeutic activ- Materials-Restriction and other enzymes were from Boehringer ity. RNA (10 p g ) and antisense probe Expression of several neuroendocrine peptide genes is known to increase in response to cAMP and/or phorbol esters [6,7,8,9], effects which, a priori, might be expected to be antagonized by lithium [2,3,4,5]. The hybrids were digested with 50 units of S1 nuclease (Boehringer Mannheim), and the products were analyzed on a sequencing gel. RNA blot hybridization was amines dopamine and norepinephrine and can be induced to performed as described [24].NT/N mRNA was detected with a canine.
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