title: Augmented cystine-glutamate exchange by pituitary adenylate cyclase-activating polypeptide signaling via the VPAC1 receptor.
abstract: In the central nervous system, cystine import in exchange for glutamate through system xc- is critical for the production of the antioxidant glutathione by astrocytes, as well as the maintenance of extracellular glutamate. Therefore, regulation of system xc- activity affects multiple aspects of cellular physiology and may contribute to disease states. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuronally derived peptide that has already been demonstrated to modulate multiple aspects of glutamate signaling suggesting PACAP may also target activity of cystine-glutamate exchange via system xc-. In this study, 24-h treatment of primary cortical cultures containing neurons and glia with PACAP concentration-dependently increased system xc- function as measured by radiolabeled cystine uptake. Furthermore, the increase in cystine uptake was completely abolished by the system xc- inhibitor, (S)-4-carboxyphenylglycine (CPG), attributing increases in cystine uptake specifically to system xc- activity. Time course and quantitative PCR results indicate that PACAP signaling may increase cystine-glutamate exchange by increasing expression of xCT, the catalytic subunit of system xc-. Furthermore, the potentiation of system xc- activity by PACAP occurs via a PKA-dependent pathway that is not mediated by the PAC1R, but rather the shared vasoactive intestinal polypeptide receptor VPAC1R. Finally, assessment of neuronal, astrocytic, and microglial-enriched cultures demonstrated that only astrocyte-enriched cultures exhibit enhanced cystine uptake following both PACAP and VIP treatment. These data introduce a novel mechanism by which both PACAP and VIP regulate system xc- activity. Synapse 68:604-612, 2014. © 2014 Wiley Periodicals, Inc.
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, 53201.
authors: Jon M
authors: JM
authors: Resch
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, 53201.
authors: Rebecca
authors: R
authors: Albano
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, 53201.
authors: Xiaoqian
authors: X
authors: Liu
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, 53201.
authors: Julie
authors: J
authors: Hjelmhaug
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, 53201.
authors: Doug
authors: D
authors: Lobner
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, 53201.
authors: David A
authors: DA
authors: Baker
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, 53201.
authors: Sujean
authors: S
authors: Choi
keywords: PACAP; VIP; astrocyte; system 
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