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Transcriptional landscapes at the intersection of neuronal apoptosis and substance P-induced survival: exploring pathways and drug targets

View Article: PubMed Central - PubMed

ABSTRACT

A change in the delicate equilibrium between apoptosis and survival regulates the neurons fate during the development of nervous system and its homeostasis in adulthood. Signaling pathways promoting or protecting from apoptosis are activated by multiple signals, including those elicited by neurotrophic factors, and depend upon specific transcriptional programs. To decipher the rescue program induced by substance P (SP) in cerebellar granule neurons, we analyzed their whole-genome expression profiles after induction of apoptosis and treatment with SP. Transcriptional pathways associated with the survival effect of SP included genes encoding for proteins that may act as pharmacological targets. Inhibition of one of these, the Myc pro-oncogene by treatment with 10058-F4, reverted in a dose-dependent manner the rescue effect of SP. In addition to elucidate the transcriptional mechanisms at the intersection of neuronal apoptosis and survival, our systems biology-based perspective paves the way towards an innovative pharmacology based on targets downstream of neurotrophic factor receptors.

No MeSH data available.


Related in: MedlinePlus

Ion homeostasis. Ca2+ homeostasis is regulated by several transporters. Ca2+ influx is primarily mediated by voltage-gated Ca2+ channels (VGCCs), transient receptor potential channels (TRPs) and ligand-gated channels. Ca2+ efflux is achieved by plasma membrane Ca2+ ATPases (PMCAs), sodium calcium exchangers (NCXs) or Na+/NCKX. Release of Ca2+ from the ER/SR is mediated through IP3 or ryanodine receptors. Store-operated channels are activated by stromal interaction molecule 1 (STIM1) protein that senses the store depletion and triggers the opening of the Ca2+-release-activated Ca2+ channels and calcium release-activated calcium modulators. Store-operated channels entry (SOCE) is also modulated by K+-permeable channels, KCa and Kv, which are regulated by intracellular Ca2+ and depolarization, respectively. These two channels help sustain SOCE generation by inducing cell hyperpolarization. Additionally, the Na+-permeable channel transient receptor potential cation channel subfamily M member (TRPM) is gated by intracellular Ca2+ and reduces Ca2+ mobilization. The reuptake of Ca2+ into the ER/SR is primarily mediated by sarcoplasmic/ER Ca2+ ATPase. Pathway objects and links are described separately in Supplementary Figure 16.
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fig3: Ion homeostasis. Ca2+ homeostasis is regulated by several transporters. Ca2+ influx is primarily mediated by voltage-gated Ca2+ channels (VGCCs), transient receptor potential channels (TRPs) and ligand-gated channels. Ca2+ efflux is achieved by plasma membrane Ca2+ ATPases (PMCAs), sodium calcium exchangers (NCXs) or Na+/NCKX. Release of Ca2+ from the ER/SR is mediated through IP3 or ryanodine receptors. Store-operated channels are activated by stromal interaction molecule 1 (STIM1) protein that senses the store depletion and triggers the opening of the Ca2+-release-activated Ca2+ channels and calcium release-activated calcium modulators. Store-operated channels entry (SOCE) is also modulated by K+-permeable channels, KCa and Kv, which are regulated by intracellular Ca2+ and depolarization, respectively. These two channels help sustain SOCE generation by inducing cell hyperpolarization. Additionally, the Na+-permeable channel transient receptor potential cation channel subfamily M member (TRPM) is gated by intracellular Ca2+ and reduces Ca2+ mobilization. The reuptake of Ca2+ into the ER/SR is primarily mediated by sarcoplasmic/ER Ca2+ ATPase. Pathway objects and links are described separately in Supplementary Figure 16.

Mentions: A total of 95 statistically significant pathways were identified in the context of SRGs (Supplementary Data S9). To reduce redundancy of deregulated pathways and simplify their comprehension, the most significant variations implicated in these pathways were summarized in Figures 2,3,4,5,6,7,8 and Supplementary Figures 9–15.


Transcriptional landscapes at the intersection of neuronal apoptosis and substance P-induced survival: exploring pathways and drug targets
Ion homeostasis. Ca2+ homeostasis is regulated by several transporters. Ca2+ influx is primarily mediated by voltage-gated Ca2+ channels (VGCCs), transient receptor potential channels (TRPs) and ligand-gated channels. Ca2+ efflux is achieved by plasma membrane Ca2+ ATPases (PMCAs), sodium calcium exchangers (NCXs) or Na+/NCKX. Release of Ca2+ from the ER/SR is mediated through IP3 or ryanodine receptors. Store-operated channels are activated by stromal interaction molecule 1 (STIM1) protein that senses the store depletion and triggers the opening of the Ca2+-release-activated Ca2+ channels and calcium release-activated calcium modulators. Store-operated channels entry (SOCE) is also modulated by K+-permeable channels, KCa and Kv, which are regulated by intracellular Ca2+ and depolarization, respectively. These two channels help sustain SOCE generation by inducing cell hyperpolarization. Additionally, the Na+-permeable channel transient receptor potential cation channel subfamily M member (TRPM) is gated by intracellular Ca2+ and reduces Ca2+ mobilization. The reuptake of Ca2+ into the ER/SR is primarily mediated by sarcoplasmic/ER Ca2+ ATPase. Pathway objects and links are described separately in Supplementary Figure 16.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979452&req=5

fig3: Ion homeostasis. Ca2+ homeostasis is regulated by several transporters. Ca2+ influx is primarily mediated by voltage-gated Ca2+ channels (VGCCs), transient receptor potential channels (TRPs) and ligand-gated channels. Ca2+ efflux is achieved by plasma membrane Ca2+ ATPases (PMCAs), sodium calcium exchangers (NCXs) or Na+/NCKX. Release of Ca2+ from the ER/SR is mediated through IP3 or ryanodine receptors. Store-operated channels are activated by stromal interaction molecule 1 (STIM1) protein that senses the store depletion and triggers the opening of the Ca2+-release-activated Ca2+ channels and calcium release-activated calcium modulators. Store-operated channels entry (SOCE) is also modulated by K+-permeable channels, KCa and Kv, which are regulated by intracellular Ca2+ and depolarization, respectively. These two channels help sustain SOCE generation by inducing cell hyperpolarization. Additionally, the Na+-permeable channel transient receptor potential cation channel subfamily M member (TRPM) is gated by intracellular Ca2+ and reduces Ca2+ mobilization. The reuptake of Ca2+ into the ER/SR is primarily mediated by sarcoplasmic/ER Ca2+ ATPase. Pathway objects and links are described separately in Supplementary Figure 16.
Mentions: A total of 95 statistically significant pathways were identified in the context of SRGs (Supplementary Data S9). To reduce redundancy of deregulated pathways and simplify their comprehension, the most significant variations implicated in these pathways were summarized in Figures 2,3,4,5,6,7,8 and Supplementary Figures 9–15.

View Article: PubMed Central - PubMed

ABSTRACT

A change in the delicate equilibrium between apoptosis and survival regulates the neurons fate during the development of nervous system and its homeostasis in adulthood. Signaling pathways promoting or protecting from apoptosis are activated by multiple signals, including those elicited by neurotrophic factors, and depend upon specific transcriptional programs. To decipher the rescue program induced by substance P (SP) in cerebellar granule neurons, we analyzed their whole-genome expression profiles after induction of apoptosis and treatment with SP. Transcriptional pathways associated with the survival effect of SP included genes encoding for proteins that may act as pharmacological targets. Inhibition of one of these, the Myc pro-oncogene by treatment with 10058-F4, reverted in a dose-dependent manner the rescue effect of SP. In addition to elucidate the transcriptional mechanisms at the intersection of neuronal apoptosis and survival, our systems biology-based perspective paves the way towards an innovative pharmacology based on targets downstream of neurotrophic factor receptors.

No MeSH data available.


Related in: MedlinePlus