Essential Role of Hrs in Endocytic Recycling of Full-length TrkB Receptor but Not Its Isoform TrkB.T1

Huang, Shuhong; Zhao, Ling; Sun, Zongpeng; Li, Xuezhi; Zhao, Guanghui; Zhang, Kaidi; Chao, Moses V.; Chen, Zhe-Yu

doi:10.1074/jbc.m809763200

Cited by 48 publications

(78 citation statements)

References 69 publications

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“…2 A, ES trace). Blocking TrkB receptor activation by the pan-Trk inhibitor, K252a, and transfection of a truncated TrkB receptor, TrkB-T1, which lacks intrinsic tyrosine kinase activity (Bredt and Nicoll, 2003) and inhibits the activation of downstream signal pathways (Huang et al, 2009), both abolished the enhancing effect of BDNF on I 6.0 (Fig. 2 B).…”

Section: Pi3k/akt Pathway Upregulates the Activity Of Asic1a Channelmentioning

confidence: 90%

PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

et al. 2012

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Central neural plasticity plays a key role in pain hypersensitivity. This process is modulated by brain-derived neurotrophic factor (BDNF) and also involves the type 1a acid-sensing ion channel (ASIC1a). However, the interactions between the BDNF receptor, tropomyosinrelated kinase B (TrkB), and ASIC1a are unclear. Here, we show that deletion of ASIC1 gene suppressed the sustained mechanical hyperalgesia induced by intrathecal BDNF application in mice. In both rat spinal dorsal horn neurons and heterologous cell cultures, the BDNF/TrkB pathway enhanced ASIC1a currents via phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) cascade and phosphorylation of cytoplasmic residue Ser-25 of ASIC1a, resulting in enhanced forward trafficking and increased surface expression. Moreover, in both rats and mice, this enhanced ASIC1a activity was required for BDNF-mediated hypersensitivity of spinal dorsal horn nociceptive neurons and central mechanical hyperalgesia, a process that was abolished by intrathecal application of a peptide representing the N-terminal region of ASIC1a encompassing Ser-25. Thus, our results reveal a novel mechanism underlying central sensitization and pain hypersensitivity, and reinforce the critical role of ASIC1a channels in these processes.

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Section: Pi3k/akt Pathway Upregulates the Activity Of Asic1a Channelmentioning

confidence: 90%

PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

et al. 2012

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“…Next, we investigated whether Myo5a participated in the postendocytic recycling of TrkB-FL. We used a live-cell ratiometric fluorescence-based recycling assay, which has been widely used in our previous studies (Chen et al, 2005;Huang et al, 2009;Huang et al, 2013), to measure the recycling levels of TrkB-FL (Fig. 4A).…”

Section: Myo5a Is Not Involved In Bdnf-dependent Trkb-fl Internalizationmentioning

confidence: 99%

Myosin5a mediates BDNF-induced postendocytic recycling of full-length TrkB and its translocation into dendritic spines

Sui

Huang

Wang

et al. 2015

Journal of Cell Science

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Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival, neurite outgrowth and synaptic plasticity by activating the receptor tropomyosin receptor kinase B (TrkB, also known as NTRK2). TrkB has been shown to undergo recycling after BDNF stimulation. We have previously reported that full-length TrkB (TrkB-FL) are recycled through a Rab11-dependent pathway upon BDNF stimuli, which is important for the translocation of TrkB-FL into dendritic spines and for the maintenance of prolonged BDNF downstream signaling during long-term potentiation (LTP). However, the identity of the motor protein that mediates the local transfer of recycled TrkB-FL back to the plasma membrane remains unclear. Here, we report that the F-actin-based motor protein myosin Va (Myo5a) mediates the postendocytic recycling of TrkB-FL. Blocking the interaction between Rab11 and Myo5a by use of a TAT-tagged peptide consisting of amino acids 55-66 of the Myo5a ExonE domain weakened the association between TrkB-FL and Myo5a and thus impaired TrkB-FL recycling and BDNF-induced TrkB-FL translocation into dendritic spines. Finally, inhibiting Myo5a-mediated TrkB-FL recycling led to a significant reduction in prolonged BDNF downstream signaling. Taken together, these results show that Myo5a mediates BDNF-dependent TrkB-FL recycling and contributes to BDNF-induced TrkB spine translocation and prolonged downstream signaling.

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“…The rapid degradation of TrkB could be caused by a fast degradation of TrkB by lysosomes. Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) binds TrkB upon BDNF stimulation to regulate the sorting of TrkB to lysosomes, and overexpression of Hrs can reduce TrkB degradation (36,37). Hrs also interacts with Hap1 to stabilize EGF receptor (20).…”

Section: Neuronal Ahi1 Deficiency Impairs Trkb Internalization and Prmentioning

confidence: 99%

Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype

Yang

Lin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies suggest that the human Abelson helper integration site-1 (AHI1) gene on chromosome 6 is associated with susceptibility to schizophrenia and autism, two common neuropsychological disorders with depression symptoms. Mouse Ahi1 protein is abundant in the hypothalamus and amygdala, which are important brain regions for controlling emotion. However, the neuronal function of Ahi1 remains unclear. With the Cre-loxP system, we created a mouse model that selectively reduces Ahi1 expression in neuronal cells. Mice with neuronal Ahi1 deficiency show reduced TrkB level in the brain and depressive phenotypes, which can be alleviated by antidepressant drugs or by overexpression of TrkB in the amygdala. Ahi1 deficiency promotes the degradation of endocytic TrkB and reduces TrkB signaling in neuronal cells. Our findings suggest that impaired endocytic sorting and increased degradation of TrkB can induce depression and that this impaired pathway may serve as a previously uncharacterized therapeutic target for depression.neuropathology | neuropsychiatric | neurotrophic | endocytosis | trafficking

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Essential Role of Hrs in Endocytic Recycling of Full-length TrkB Receptor but Not Its Isoform TrkB.T1

Cited by 48 publications

References 69 publications

PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

Myosin5a mediates BDNF-induced postendocytic recycling of full-length TrkB and its translocation into dendritic spines

Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype

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