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IA-2 modulates dopamine secretion in PC12 cells.

ABSTRACT: The secretion of the hormone insulin from beta cells is modulated by the expression of the dense core vesicle transmembrane protein IA-2. Since IA-2 is found in neuroendocrine cells throughout the body, the present experiments were initiated to determine whether the expression of IA-2 also modulates the secretion of neurotransmitters. Using the dopamine-secreting pheochromocytoma cell line PC12, we found that the overexpressions of IA-2 increased the cellular content and secretion of dopamine, whereas the knockdown of IA-2 by siRNA decreased the cellular content and secretion of dopamine. Neither the overexpression nor knockdown of IA-2 influenced the uptake of [H(3)]dopamine by PC12 cells, but did influence the amount of [H(3)]dopamine secreted. Overexpression of IA-2 also increased the level of the dense core vesicle-associated proteins Rab3A, IA-2beta and secretogranin II, whereas the knockdown of IA-2 decreased the level of these proteins. We conclude that the expression of IA-2 profoundly influences the function of dense core vesicles and has a broad modulating effect on the cellular content and secretion of both hormones and neurotransmitters.

SUBMITTER: Nishimura T

PROVIDER: S-EPMC3495171 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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IA-2 modulates dopamine secretion in PC12 cells.

Nishimura Takuya T Harashima Shin-Ichi S Yafang Hu H Notkins Abner Louis AL

Molecular and cellular endocrinology 20090930 1-2

The secretion of the hormone insulin from beta cells is modulated by the expression of the dense core vesicle transmembrane protein IA-2. Since IA-2 is found in neuroendocrine cells throughout the body, the present experiments were initiated to determine whether the expression of IA-2 also modulates the secretion of neurotransmitters. Using the dopamine-secreting pheochromocytoma cell line PC12, we found that the overexpressions of IA-2 increased the cellular content and secretion of dopamine, w ...[more]

PMID: 19799965

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Project description:Polychlorinated biphenyls (PCB) exposure at low chronic levels is a significant public health concern. Animal and epidemiological studies indicate that low PCB body burden may cause neurotoxicity and be a risk factor for neurodegenerative diseases. In the current study, we measured the ability of two non-dioxin like PCBs, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and 2,2'3,5',6-pentachlorobiphenyl (PCB95), to alter dopamine (DA) levels and metabolism using the dopaminergic PC12 cell line. Our hypothesis is that treatment of PC12 cells with non-toxic concentrations of PCB153 or PCB95 for 12 and 24 h will have different effects due to different congener structures. Levels of DA and of 3,4-dihydroxyphenylacetaldehyde (DOPAL), 3, 4-dihyroxylphenylethanol (DOPET), and 3,4-dihyroxylphenylacetic acid (DOPAC) metabolite, gene expression of the dopamine synthesis enzyme tyrosine hydroxylase (TH) and the vesicular monoamine transporter (VMAT2), and gene expression of the anti-oxidant enzymes Cu/Zn and Mn superoxide oxidase (Cu/ZnSOD, MnSOD), glutathione peroxidase (GPx) and catalase were determined. PCB153 decreased intracellular and extracellular levels of DA after 12 h exposure and this was consistent with an increase in DA metabolites. After 24 h, the level of DA in medium increased compared to the control. In contrast, PCB95 exposure increased the intracellular DA level and decreased DA in medium consistent with a down-regulation of VMAT2 expression at 12 h. After 24 h exposure, PCB95 increased DA levels in media. Expression of TH mRNA increased slightly following 12 h but not at 24 h exposure. MnSOD mRNA increased up to 6-7 fold and Cu/ZnSOD increased less than two-fold after treatment with both congeners. Catalase expression was up-regulated following 24 h exposure to PCB153 and PCB95, but GPx expression was down-regulated after 12 h exposure to PCB95 only. These results suggest that PCB153 and PCB95 are neurotoxic and affect DA turnover with structure-dependent differences between these two congeners.

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IA-2 modulates dopamine secretion in PC12 cells.

Publications

IA-2 modulates dopamine secretion in PC12 cells.

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