Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuron-derived peptide regulating glial glutamate transport and metabolism.
In the brain, glutamatergic neurotransmission is terminated predominantly by the rapid uptake of synaptically released glutamate into astrocytes through the Na(+)-dependent glutamate transporters GLT-1 and GLAST and its subsequent conversion into glutamine by the enzyme glutamine synthetase (GS). To date, several factors have been identified that rapidly alter glial glutamate uptake by post-translational modification of glutamate transporters. The only condition known to affect the expression of glial glutamate transporters and GS is the coculturing of glia with neurons. We now demonstrate that neurons regulate glial glutamate turnover via pituitary adenylate cyclase-activating polypeptide (PACAP). In the cerebral cortex PACAP is synthesized by neurons and acts on the subpopulation of astroglia involved in glutamate turnover. Exposure of astroglia to PACAP increased the maximal velocity of [(3)H]glutamate uptake by promoting the expression of GLT-1, GLAST, and GS. Moreover, the stimulatory effects of neuron-conditioned medium on glial glutamate transporter expression were attenuated in the presence of PACAP-inactivating antibodies or the PACAP receptor antagonist PACAP 6-38. In contrast to PACAP, vasoactive intestinal peptide promoted glutamate transporter expression only at distinctly higher concentrations, suggesting that PACAP exerts its effects on glial glutamate turnover via PAC1 receptors. Although PAC1 receptor-dependent activation of protein kinase A (PKA) was sufficient to promote the expression of GLAST, the activation of both PKA and protein kinase C (PKC) was required to promote GLT-1 expression optimally. Given the existence of various PAC1 receptor isoforms that activate PKA and PKC to different levels, these findings point to a complex mechanism by which PACAP regulates glial glutamate transport and metabolism. Disturbances of these regulatory mechanisms could represent a major cause for glutamate-associated neurological and psychiatric disorders.
Figiel
M
M
Anatomie und Zellbiologie, Universität Ulm, 89069 Ulm, Germany.
Engele
J
J
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001692:Biological Transport / Q000502:physiology; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D018698:Glutamic Acid / Q000493:pharmacokinetics*; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000737:chemistry / Q000201:enzymology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; C495402:Adcyap1 protein, mouse; C495403:Adcyap1 protein, rat; C495504:Adcyap1r1 protein, mouse; C495505:Adcyap1r1 protein, rat; D027322:Amino Acid Transport System X-AG; D017931:DNA Primers; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone; D014660:Vasoactive Intestinal Peptide; D018698:Glutamic Acid; D003994:Bucladesine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D005974:Glutamate-Ammonia Ligase