title: Pituitary Adenylate cyclase-activating polypeptide orchestrates neuronal regulation of the astrocytic glutamate-releasing mechanism system xc (.).
abstract: Glutamate signaling is achieved by an elaborate network involving neurons and astrocytes. Hence, it is critical to better understand how neurons and astrocytes interact to coordinate the cellular regulation of glutamate signaling. In these studies, we used rat cortical cell cultures to examine whether neurons or releasable neuronal factors were capable of regulating system xc (-) (Sxc), a glutamate-releasing mechanism that is expressed primarily by astrocytes and has been shown to regulate synaptic transmission. We found that astrocytes cultured with neurons or exposed to neuronal-conditioned media displayed significantly higher levels of Sxc activity. Next, we demonstrated that the pituitary adenylate cyclase-activating polypeptide (PACAP) may be a neuronal factor capable of regulating astrocytes. In support, we found that PACAP expression was restricted to neurons, and that PACAP receptors were expressed in astrocytes. Interestingly, blockade of PACAP receptors in cultures comprised of astrocytes and neurons significantly decreased Sxc activity to the level observed in purified astrocytes, whereas application of PACAP to purified astrocytes increased Sxc activity to the level observed in cultures comprised of neurons and astrocytes. Collectively, these data reveal that neurons coordinate the actions of glutamate-related mechanisms expressed by astrocytes, such as Sxc, a process that likely involves PACAP. A critical gap in modeling excitatory signaling is how distinct components of the glutamate system expressed by neurons and astrocytes are coordinated. In these studies, we found that system xc (-) (Sxc), a glutamate release mechanism expressed by astrocytes, is regulated by releasable neuronal factors including PACAP. This represents a novel form of neuron-astrocyte communication, and highlights the possibility that pathological changes involving astrocytic Sxc may stem from altered neuronal activity.
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, USA.
authors: Linghai
authors: L
authors: Kong
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, USA.
authors: Rebecca
authors: R
authors: Albano
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, USA.
authors: Aric
authors: A
authors: Madayag
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, USA.
authors: Nicholas
authors: N
authors: Raddatz
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, USA.
authors: John R
authors: JR
authors: Mantsch
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, USA.
authors: SuJean
authors: S
authors: Choi
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, USA.
authors: Doug
authors: D
authors: Lobner
authors: Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, USA.
authors: David A
authors: DA
authors: Baker
mesh_terms: D026922:Amino Acid Transport Systems, Acidic; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D003553:Cystine / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000096:biosynthesis / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000096:biosynthesis / Q000235:genetics; D009435:Synaptic Transmission / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics; D027182:Amino Acid Transport System y+
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D003553:Cystine; D018698:Glutamic Acid; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; C000723960:Slc7a11 protein, rat; D027182:Amino Acid Transport System y+
keywords: PACAP; astrocyte; cystine; glutamate; neuron-astrocyte interaction; system xc−