Glutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals

Abstract

Tissue-type plasminogen activator (tPA) regulates physiological processes in the brain, such as learning and memory, and plays a critical role in neuronal survival and neuroinflammation in pathological conditions. Here we demonstrate, by combining mouse in vitro and in vivo data, that tPA is an important element of the cross talk between neurons and astrocytes. The data show that tPA released by neurons is constitutively endocytosed by astrocytes via the low-density lipoprotein-related protein receptor, and is then exocytosed in a regulated manner. The exocytotic recycling of tPA by astrocytes is inhibited in the presence of extracellular glutamate. Kainate receptors of astrocytes act as sensors of extracellular glutamate and, via a signaling pathway involving protein kinase C, modulate the exocytosis of tPA. Further, by thus capturing extracellular tPA, astrocytes serve to reduce NMDA-mediated responses potentiated by tPA. Overall, this work provides the first demonstration that the neuromodulator, tPA, may also be considered as a gliotransmitter.

LRP-1 modulates glutamate-induced phase shifting in the mouse SCN circadian clock

“…LRP1 has been shown to regulate levels of tPA in other systems. LRP1 endocytic activity has been shown to clear tPA from extracellular space to maintain appropriate levels (10), and regulate tPA mRNA and protein transcription through an uncharacterized pathway. In mixed neuronal/astrocyte cell cultures neurons release tPA and then astrocytes endocytose tPA in an LRP1 dependent manner [10].…”

“…LRP1 endocytic activity has been shown to clear tPA from extracellular space to maintain appropriate levels (10), and regulate tPA mRNA and protein transcription through an uncharacterized pathway. In mixed neuronal/astrocyte cell cultures neurons release tPA and then astrocytes endocytose tPA in an LRP1 dependent manner [10]. tPA is then exocytosed in a regulated manner, and glutamate inhibits this recycling of tPA from astrocytes [10].…”

“…In mixed neuronal/astrocyte cell cultures neurons release tPA and then astrocytes endocytose tPA in an LRP1 dependent manner [10]. tPA is then exocytosed in a regulated manner, and glutamate inhibits this recycling of tPA from astrocytes [10]. LRP1-mediated endocytosis can either target ligands to the lysosomal pathway for degradation or facilitate recycling of the ligand back to the extracellular space [4].…”

“…LRP1-mediated endocytosis can either target ligands to the lysosomal pathway for degradation or facilitate recycling of the ligand back to the extracellular space [4]. tPA potentiates NMDA responses, and by capturing extracellular tPA astrocytes reduce NMDA mediated responses [10]. In the SCN, glutamate release is increased during the day and decreased at night and total levels of tPA are rhythmic, being high at night and low during the day [3].…”

“…LRP1 is required for NMDA-R surface localization and LRP1 works in a unique complex with NMDAR and Trk receptors to modulate signaling in response to specific ligands [6]. Signaling events through LRP1 are different for individual ligands, and signaling events linked to tPA include activation of Mek1, Erk 1 and 2, and protein kinase A (PKA), which all participate in circadian clock regulation (4,10). Since NMDAR, TrkB, and now LRP1 appear to be critical for phase shifting in the SCN circadian clock, it is possible that these proteins work in concert to modulate signaling in response to specific ligands to regulate phase shifting.…”