scholarly journals Stimulation of neuropeptide Y gene expression by brain-derived neurotrophic factor requires both the phospholipase Cγ and Shc binding sites on its receptor, TrkB

1998 ◽  
Vol 333 (3) ◽  
pp. 505-509 ◽  
Author(s):  
Alan G. WILLIAMS ◽  
Andrew C. HARGREAVES ◽  
Frank J. GUNN-MOORE ◽  
Jeremy M. TAVARÉ
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Neuropeptide Y ◽  
Map Kinase ◽  
Pc12 Cells ◽  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Luciferase Expression ◽  
High Affinity ◽  
Stimulation Of

In PC12 cells, it has been previously reported that nerve growth factor stimulates neuropeptide Y (NPY) gene expression. In the current study we examined the signalling pathways involved in this effect by transiently expressing in PC12 cells the receptor (TrkB) for the related neurotrophin, brain-derived neurotrophic factor (BDNF). BDNF caused a 3-fold induction of luciferase expression from a transiently co-transfected plasmid possessing the firefly luciferase gene under the control of the NPY promoter. This effect of BDNF was completely blocked by either a Y484F mutation in TrkB (which blocks high-affinity Shc binding to TrkB) or by a Y785F substitution [which blocks the binding, phosphorylation and activation of phospholipase Cγ (PLCγ)]. Activation of the NPY promoter by neurotrophin-3 in PC12 cells overexpressing TrkC was also completely blocked by a naturally occurring kinase insert which prevents the high-affinity binding of Shc and PLCγ. NPY promoter activation by BDNF was blocked by PD98059, suggesting a role for mitogen-activated protein kinase (MAP kinase). Stimulation of NPY gene expression by PMA, but not by BDNF, was blocked by Ro-31-8220, a protein kinase C inhibitor, excluding a role for this serine/threonine protein kinase in the effect of BDNF. In addition, BDNF did not cause an elevation in cytosolic Ca2+ concentration. Taken together, our results suggest that stimulation of the NPY promoter by BDNF requires the simultaneous activation of two distinct pathways; one involves Shc and MAP kinase, and the other appears to be PLCγ-independent but requires an intact tyrosine-785 on TrkB and so may involve an effector of TrkB signalling that remains to be identified.

Brain-derived neurotrophic factor stimulation of T-type Ca2+ channels in sensory neurons contributes to increased peripheral pain sensitivity

2019 ◽  
Vol 12 (600) ◽  
pp. eaaw2300 ◽  
Author(s):  
Hua Wang ◽  
Yuan Wei ◽  
Yichen Pu ◽  
Dongsheng Jiang ◽  
Xinghong Jiang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Sensory Neurons ◽  
Neurotrophic Factor ◽  
Pain Sensitivity ◽  
Neuronal Excitability ◽  
Brain Derived Neurotrophic Factor ◽  
Mitogen Activated Protein Kinase ◽  
Mechanical Stimuli ◽  
Action Potential Firing ◽  
Stimulation Of

Although brain-derived neurotrophic factor (BDNF) is implicated in the nociceptive signaling of peripheral sensory neurons, the underlying mechanisms remain largely unknown. Here, we elucidated the effects of BDNF on the neuronal excitability of trigeminal ganglion (TG) neurons and the pain sensitivity of rats mediated by T-type Ca2+ channels. BDNF reversibly and dose-dependently enhanced T-type channel currents through the activation of tropomyosin receptor kinase B (TrkB). Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its downstream target, the kinase AKT, abolished the BDNF-induced T-type channel response. BDNF application activated p38 mitogen-activated protein kinase (MAPK), and this effect was prevented by inhibition of PI3K but not of protein kinase A (PKA). Antagonism of either PI3K or p38 MAPK prevented the BDNF-induced stimulation of PKA activity, whereas PKA inhibition blocked the BDNF-mediated increase in T-type currents. BDNF increased the rate of action potential firing in TG neurons and enhanced the pain sensitivity of rats to mechanical stimuli. Moreover, inhibition of TrkB signaling abolished the increased mechanical sensitivity in a rat model of chronic inflammatory pain, and this effect was attenuated by either T-type channel blockade or knockdown of the channel Cav3.2. Together, our findings indicate that BDNF enhances T-type currents through the stimulation of TrkB coupled to PI3K-p38-PKA signaling, thereby inducing neuronal hyperexcitability of TG neurons and pain hypersensitivity in rats.

Hypothalamic neuropeptide gene expression during recovery from food restriction superimposed on short-day photoperiod-induced weight loss in the Siberian hamster

2007 ◽  
Vol 293 (3) ◽  
pp. R1094-R1101 ◽  
Author(s):  
Zoë A. Archer ◽  
Kim M. Moar ◽  
Tracy J. Logie ◽  
Laura Reilly ◽  
Valerie Stevens ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Loss ◽  
Energy Balance ◽  
Neuropeptide Y ◽  
Caloric Restriction ◽  
Neurotrophic Factor ◽  
Food Restriction ◽  
Brain Derived Neurotrophic Factor ◽  
Related Peptide ◽  
Short Day

Previously, 40% food restriction of male Siberian hamsters over 21 days in short-day (SD) photoperiod induced characteristic changes in expression of hypothalamic arcuate nucleus energy balance genes; mRNAs for neuropeptide Y, agouti-related peptide, and leptin receptor were upregulated, and those of proopiomelanocortin and cocaine- and amphetamine-regulated transcript were depressed. The present study examined the effect of refeeding hamsters for 6 days (∼50% recovery of weight differential) or 19 days (resumption of appropriate weight trajectory). Hyperphagia continued throughout refeeding, but differences in fat pad weights and leptin levels had disappeared after 19 days. Cocaine- and amphetamine-regulated transcript gene expression was depressed by prior restriction in both refed groups. The depressive effect of prior restriction on proopiomelanocortin gene expression had disappeared after 19 days of refeeding. There was no effect of prior food restriction on neuropeptide Y or agouti-related peptide gene expression. Expression of the anorexigenic brain-derived neurotrophic factor was downregulated in the ventromedial nucleus after SD exposure for 12 wk. In the SD food restriction study, there were effects of photoperiod on brain-derived neurotrophic factor gene expression but not of prior food restriction. Hypothalamic energy balance genes in the hamster respond asynchronously to return to a seasonally appropriate body weight. The achievement of this weight rather than the weight at which caloric restriction was imposed is the critical factor. The differential responses of hypothalamic energy balance genes to food restriction and refeeding are poorly characterized in any species, a critical issue given their potential relevance to human weight loss strategies that involve caloric restriction.

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