Document Type
Article
Language
eng
Publication Date
12-2014
Publisher
Wiley
Source Publication
Synapse
Source ISSN
0887-4476
Original Item ID
DOI: 10.1002/syn.21772
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.
Recommended Citation
Resch, Jon M.; Albano, Rebecca; Liu, Xiaoqian; Hjelmhaug, Julie; Lobner, Doug; Baker, David A.; and Choi, Sujean, "Augmented Cystine–Glutamate Exchange by Pituitary Adenylate Cyclase-activating Polypeptide Signaling via the VPAC1 Receptor" (2014). Biomedical Sciences Faculty Research and Publications. 120.
https://epublications.marquette.edu/biomedsci_fac/120
Comments
Accepted version. Synapse, Vol. 68, No. 12 (December 2014): 604-612. This is the peer reviewed version of the following article: "Augmented Cystine–Glutamate Exchange by Pituitary Adenylate Cyclase-activating Polypeptide Signaling via the VPAC1 Receptor," which has been published in final form at DOI. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for self-archiving. © 2014 Wiley. Used with permission.