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Augmented cystine–glutamate exchange by pituitary adenylate cyclase‐activating polypeptide signaling via the VPAC1 receptor
Author(s) -
Resch Jon M.,
Albano Rebecca,
Liu Xiaoqian,
Hjelmhaug Julie,
Lobner Doug,
Baker David A.,
Choi Sujean
Publication year - 2014
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.21772
Subject(s) - glutamate receptor , cystine , microbiology and biotechnology , vasoactive intestinal peptide , astrocyte , adenylate kinase , chemistry , biochemistry , biology , receptor , neuropeptide , central nervous system , neuroscience , cysteine , enzyme
In the central nervous system, cystine import in exchange for glutamate through systemx c −is critical for the production of the antioxidant glutathione by astrocytes, as well as the maintenance of extracellular glutamate. Therefore, regulation of systemx 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 systemx c − . In this study, 24‐h treatment of primary cortical cultures containing neurons and glia with PACAP concentration‐dependently increased systemx c −function as measured by radiolabeled cystine uptake. Furthermore, the increase in cystine uptake was completely abolished by the systemx c −inhibitor, ( S )‐4‐carboxyphenylglycine (CPG), attributing increases in cystine uptake specifically to systemx 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 systemx c − . Furthermore, the potentiation of systemx 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. These data introduce a novel mechanism by which both PACAP and VIP regulate systemx c −activity. Synapse 68:604–612, 2014 . © 2014 Wiley Periodicals, Inc.