The primary neurotransmitters targeted by currently used antidepressants, such as duloxetine, venlafaxine and fluoxetine, are serotonin and norepinephrine, which also are released in significant amounts in the central...The primary neurotransmitters targeted by currently used antidepressants, such as duloxetine, venlafaxine and fluoxetine, are serotonin and norepinephrine, which also are released in significant amounts in the central nervous system in response to sympathetic nervous system activation. In cultured hippocampal neurons, we have previously shown that norepinephrine induces increased expression of brain-derived neurotrophic factor (BDNF), the PI-3 K/Akt, MAPK pro-survival pathways, the BDNF receptor, TrkB, a transcription factor, and cyclic AMP response element binding protein (CREB). In the present study, we extend these findings of increased BDNF expression to its kinetics of release into the surrounding media. We also evaluate these two cell survival pathways, TrkB and CREB, in response to application of serotonin and/or norepinephrine. Serotonin elicits an earlier, but brief expression and release of BDNF, whereas norepinephrine elicits a more delayed and sustained release of BDNF. In response to both norepinephrine and 5-HT, the presence of BDNF in lysates and subsequent release into the media is significantly increased out to 4 h, as is PI-3 K/Akt activation. Together, these two neurotransmitters increase BDNF expression and release covering the entire 8 h continuum evaluated. The results of this study provide further evidence for a G protein-coupled receptor and a crosstalk-to-TrkB receptor with transactivation signaling across pathways.展开更多
Medications acting as mood stabilizers work by enhancing and maintaining the concentration of circulating synaptic neurotransmitters, which then activate a plethora of various intracellular signal transduction and sec...Medications acting as mood stabilizers work by enhancing and maintaining the concentration of circulating synaptic neurotransmitters, which then activate a plethora of various intracellular signal transduction and second messenger cascades. Previously, we showed that two of these cascades, the PI-3K and MAPK pathways, are activated by cross-talk with the protein kinase A cAMP cascade and by brain-derived neurotrophic factor (BDNF), an immediate-early gene whose expression is the result of phosphorylation of the transcription factor, cAMP response element binding protein (CREB). In the current study, we extend these findings to include the protein kinase C (PKC) pathway. Western blotting studies show that application of norepinephrine to cultured hippocampal neurons leads to increased expression of BDNF, phosphorylation of CREB, activation of growth-associated protein-43 (GAP-43) and activation of PKCμ and PKCt538. Because GAP-43 is a putative substrate for PKC, the results of this study lend further support of a G-protein coupled receptor cross-talking to an entirely distinct intracellular pathway that is known to be involved in neuritogenesis.展开更多
文摘The primary neurotransmitters targeted by currently used antidepressants, such as duloxetine, venlafaxine and fluoxetine, are serotonin and norepinephrine, which also are released in significant amounts in the central nervous system in response to sympathetic nervous system activation. In cultured hippocampal neurons, we have previously shown that norepinephrine induces increased expression of brain-derived neurotrophic factor (BDNF), the PI-3 K/Akt, MAPK pro-survival pathways, the BDNF receptor, TrkB, a transcription factor, and cyclic AMP response element binding protein (CREB). In the present study, we extend these findings of increased BDNF expression to its kinetics of release into the surrounding media. We also evaluate these two cell survival pathways, TrkB and CREB, in response to application of serotonin and/or norepinephrine. Serotonin elicits an earlier, but brief expression and release of BDNF, whereas norepinephrine elicits a more delayed and sustained release of BDNF. In response to both norepinephrine and 5-HT, the presence of BDNF in lysates and subsequent release into the media is significantly increased out to 4 h, as is PI-3 K/Akt activation. Together, these two neurotransmitters increase BDNF expression and release covering the entire 8 h continuum evaluated. The results of this study provide further evidence for a G protein-coupled receptor and a crosstalk-to-TrkB receptor with transactivation signaling across pathways.
文摘Medications acting as mood stabilizers work by enhancing and maintaining the concentration of circulating synaptic neurotransmitters, which then activate a plethora of various intracellular signal transduction and second messenger cascades. Previously, we showed that two of these cascades, the PI-3K and MAPK pathways, are activated by cross-talk with the protein kinase A cAMP cascade and by brain-derived neurotrophic factor (BDNF), an immediate-early gene whose expression is the result of phosphorylation of the transcription factor, cAMP response element binding protein (CREB). In the current study, we extend these findings to include the protein kinase C (PKC) pathway. Western blotting studies show that application of norepinephrine to cultured hippocampal neurons leads to increased expression of BDNF, phosphorylation of CREB, activation of growth-associated protein-43 (GAP-43) and activation of PKCμ and PKCt538. Because GAP-43 is a putative substrate for PKC, the results of this study lend further support of a G-protein coupled receptor cross-talking to an entirely distinct intracellular pathway that is known to be involved in neuritogenesis.
