Augmented Cystine-Glutamate Exchange by Pituitary Adenylate Cyclase-Activating Polypeptide Signaling via the VPAC1 Receptor

作者：Resch Jon M; Albano Rebecca; Liu Xiaoqian; Hjelmhaug Julie; Lobner Doug; Baker David A; Choi Sujean^*

来源：Synapse, 2014, 68(12): 604-612.

DOI：10.1002/syn.21772

• PACAP
• VIP
• system x(c)(-)
• astrocyte

In the central nervous system, cystine import in exchange for glutamate through system x(c)(-) is critical for the production of the antioxidant glutathione by astrocytes, as well as the maintenance of extracellular glutamate. Therefore, regulation of system x(c)(-) 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 x(c)(-). In this study, 24-h treatment of primary cortical cultures containing neurons and glia with PACAP concentration-dependently increased system x(c)(-) function as measured by radiolabeled cystine uptake. Furthermore, the increase in cystine uptake was completely abolished by the system x(c)(-) inhibitor, (S)-4-carboxyphenylglycine (CPG), attributing increases in cystine uptake specifically to system x(c)(-) 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 x(c)(-). Furthermore, the potentiation of system x(c)(-) 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.

• 出版日期2014-12