Stathmin Phosphorylation Is Regulated in Striatal Neurons by Vasoactive Intestinal Peptide and Monoamines via Multiple Intracellular Pathways

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Abstract
Stathmin is a ubiquitous soluble protein whose phosphorylation is associated with the intracellular mechanisms involved in the regulations of cell proliferation, differentiation, and functions by extracellular effectors. It is present in the various tissues and cell types as at least two distinct isoforms in their unphosphorylated (Mr approximately 19,000; pI approximately 6.2-6.0) and increasingly phosphorylated forms. Stathmin is particularly abundant in brain, mostly because of its high concentration in neurons, where the protein is a major phosphorylation substrate. In intact striatal neurons grown in primary culture, the cyclic AMP-increasing drug forskolin and the protein kinase C-activating agent 12-O-tetradecanoylphorbol 13-acetate (TPA) induced a potent phosphorylation of stathmin. Their actions were at least partially additive, appearing actually most likely "sequential" on various phosphorylated states of stathmin. Vasoactive intestinal peptide (VIP) reproduced the forskolin-like stimulation but stimulated also other, TPA, and/or Ca2(+)-like protein phosphorylations. These actions of VIP were already maximal after 5 min and were long lasting, still important after 2 h. In addition, concentrations as low as 1 nM were enough to obtain a significant effect, on both cyclic AMP-dependent and independent phosphorylations. Dopamine and the beta-adrenergic agonist isoproterenol were also able to stimulate stathmin phosphorylation, but only with a forskolin-like pattern. Their actions were not additive to those of VIP, confirming previous results on the colocalization of both dopamine D1 and noradrenaline beta 1 receptors with VIP receptors on striatal neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

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