Modulation of Sympathetic Activity by Tissue Plasminogen Activator Is Independent of Plasminogen and Urokinase

Schäefer, Ulrich; Vorlová, Sandra; Machida, Takuji; Melchor, Jerry P.; Strickland, Sidney; Levi, Roberto

doi:10.1124/jpet.107.121335

Cited by 2 publications

(2 citation statements)

References 37 publications

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“…Given the dramatic increase in PN-1 between DIV5 and DIV12 cultures, PN-1 presents as the operative non-plasminogen substrate in this setting. This multi-factorial mechanism may underlie some of the proteolytic, yet plasmin-independent roles of tPA (Pawlak et al 2002;Yepes et al 2002Yepes et al , 2003Kumada et al 2005;Schaefer et al 2007;Park et al 2008). Finally, adding to the ways in which the plasminogen activator system can modulate the NMDAR, our analyses uncover the capacity of plasmin to discretely cleave the NR1 subunit of the NMDAR.…”

Section: Discussionmentioning

confidence: 87%

Tissue‐type plasminogen activator requires a co‐receptor to enhance NMDA receptor function

Samson¹,

Nevin²,

Croucher³

et al. 2008

Journal of Neurochemistry

104

120

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Glutamate is the main excitatory neurotransmitter of the central nervous system. Tissue-type plasminogen activator (tPA) is recognized as a modulator of glutamatergic neurotransmission. This attribute is exemplified by its ability to potentiate calcium signaling following activation of the glutamate-binding N-methyl-D-aspartate receptor (NMDAR). It has been hypothesized that tPA can directly cleave the NR1 subunit of the NMDAR and thereby potentiate NMDA-induced calcium influx. In contrast, here we show that this increase in NMDAR signaling requires tPA to be proteolytically active, but does not involve cleavage of the NR1 subunit or plasminogen. Rather, we demonstrate that enhancement of NMDAR function by tPA is mediated by a member of the Low-Density Lipoprotein Receptor (LDLR) family. Hence, this study proposes a novel functional relationship between tPA, the NMDAR, a LDLR and an unknown substrate which we suspect to be a serpin. Interestingly, whilst tPA alone failed to cleave NR1, cell-surface NMDARs did serve as an efficient and discrete proteolytic target for plasmin. Hence, plasmin and tPA can affect the NMDAR via distinct avenues. Altogether, we find that plasmin directly proteolyses the NMDAR whilst tPA functions as an indirect modulator of NMDA-induced events via LDLR engagement.

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Section: Discussionmentioning

confidence: 87%

Tissue‐type plasminogen activator requires a co‐receptor to enhance NMDA receptor function

Samson¹,

Nevin²,

Croucher³

et al. 2008

Journal of Neurochemistry

104

120

View full text Add to dashboard Cite

show abstract

“…Conversely, t-PA plays a role in sympathetic nerve function because t-PA inhibition reduced sympathetic responses of the guinea pig vas deferens and t-PA null mice were deficient in norepinephrine release. This was independent of plasminogen and attenuated by plasminogen activator inhibitor type 1 (PAI-1) (22,23).…”

Section: Peripheral Nervous Systemmentioning

confidence: 99%

Human tissue-type plasminogen activator

Kruithof¹,

Dunoyer‐Geindre²

2014

Thromb Haemost

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SummaryTissue-type plasminogen activator (t-PA ) plays an important role in the removal of intravascular fibrin deposits and has several physiological roles and pathological activities in the brain. Its production by many other cell types suggests that t-PA has additional functions outside the vascular and central nervous system. Activity of t-PA is regulated at the level of its gene transcription, its mRNA stability and translation, its storage and regulated release, its interaction with cofactors that enhance its activity, its inhibition by inhibitors such as plasminogen activator inhibitor type 1 or neuroserpin, and its removal by clearance receptors. Gene transcription of t-PA is modulated by a large number of hormones, growth factors, cytokines or drugs and t-PA gene responses may be tissue-specific. The aim of this review is to summarise current knowledge on t-PA function and regulation of its pericellular activity, with an emphasis on regulation of its gene expression.

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Modulation of Sympathetic Activity by Tissue Plasminogen Activator Is Independent of Plasminogen and Urokinase

Cited by 2 publications

References 37 publications

Tissue‐type plasminogen activator requires a co‐receptor to enhance NMDA receptor function

Tissue‐type plasminogen activator requires a co‐receptor to enhance NMDA receptor function

Human tissue-type plasminogen activator

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