Journal article
Augmented cystine–glutamate exchange by pituitary adenylate cyclase‐activating polypeptide signaling via the VPAC1 receptor
Synapse (New York, N.Y.), Vol.68(12), pp.604-612
12/2014
DOI: 10.1002/syn.21772
PMCID: PMC4309754
PMID: 25066643
Abstract
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.
24‐hour treatment of cortical cultures with pituitary adenylate cyclase‐activating polypeptide (PACAP) increases cystine (c‐c) uptake via system
xc− (↑⊕↓) function primarily in astrocytes. System
xc− is critical for facilitating the antioxidant glutathione and glutamate (Glu) signaling both of which may significantly contribute to cellular physiology, neuronal signaling, and disease states.
Details
- Title: Subtitle
- Augmented cystine–glutamate exchange by pituitary adenylate cyclase‐activating polypeptide signaling via the VPAC1 receptor
- Creators
- Jon M Resch - Marquette UniversityRebecca Albano - Marquette UniversityXiaoqian Liu - Marquette UniversityJulie Hjelmhaug - Marquette UniversityDoug Lobner - Marquette UniversityDavid A Baker - Marquette UniversitySujean Choi - Marquette University
- Resource Type
- Journal article
- Publication Details
- Synapse (New York, N.Y.), Vol.68(12), pp.604-612
- DOI
- 10.1002/syn.21772
- PMID
- 25066643
- PMCID
- PMC4309754
- NLM abbreviation
- Synapse
- ISSN
- 0887-4476
- eISSN
- 1098-2396
- Number of pages
- 9
- Grant note
- NIH (DK074734 (to S.C.) and DA017328 (to D.A.B.))
- Language
- English
- Date published
- 12/2014
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984065855002771
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