Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis

Sosanya, Natasha M.; Brager, Darrin H.; Wolfe, Sarah A.; Niere, Farr; Raab‐Graham, Kimberly F.

doi:10.1016/j.nbd.2014.09.011

Cited by 42 publications

(48 citation statements)

References 44 publications

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“…A brief one hour reduction in mTORC1 signaling was sufficient to alter the expression of select proteins bidirectionally with ϳ23% (red) and ϳ17% (yellow) increasing their expression when mTORC1 is active and inhibited, respectively (beyond Ϯ 0.5 log 2 fold change; supplemental Table S8). As expected, Kv1.1 protein (Kcna1) was only detected in the soluble fraction when mTORC1 was repressed, confirming our previous findings (31,34,35). Notably, ϳ11% of the disease-related proteins showed changes where mTORC1 activity had a different impact depending on the subcellular fraction.…”

Section: Brief Rapamycin Exposure Alters Localization and Expression supporting

confidence: 89%

“…Pharmacological antagonism of N-methyl-D-aspartate (NMDA) receptors, a subtype of glutamate receptors that lies upstream of mTOR activation, promotes the synthesis of the voltage-gated potassium channel, Kv1.1, in dendrites (34,35). Consistent with these results, in models of temporal lobe epilepsy there is a reduction in the expression of voltage-gated ion channels including Kv1.1 (30,31,36). Interestingly in a model of focal neocortical epilepsy, overexpression of Kv1.1 blocked seizure activity (37).…”

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confidence: 77%

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Analysis of Proteins That Rapidly Change Upon Mechanistic/Mammalian Target of Rapamycin Complex 1 (mTORC1) Repression Identifies Parkinson Protein 7 (PARK7) as a Novel Protein Aberrantly Expressed in Tuberous Sclerosis Complex (TSC)

Niere

Namjoshi²,

Song

et al. 2016

Molecular & Cellular Proteomics

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Many biological processes involve the mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Thus, the challenge of deciphering mTORC1-mediated functions during normal and pathological states in the central nervous system is challenging. Because mTORC1 is at the core of translation, we have investigated mTORC1 function in global and regional protein expression. Activation of mTORC1 has been generally regarded to promote translation. Few but recent works have shown that suppression of mTORC1 can also promote local protein synthesis. Moreover, excessive mTORC1 activation during diseased states represses basal and activity-induced protein synthesis. To determine the role of mTORC1 activation in protein expression, we have used an unbiased, large-scale proteomic approach. We provide evidence that a brief repression of mTORC1 activity in vivo by rapamycin has little effect globally, yet leads to a significant remodeling of synaptic proteins, in particular those proteins that reside in the postsynaptic density. We have also found that curtailing the activity of mTORC1 bidirectionally alters the expression of proteins associated with epilepsy, Alzheimer's disease, and autism spectrum disorder-neurological disorders that exhibit elevated mTORC1 activity. Through a protein-protein interaction network analysis, we have identified common proteins shared among these mTORC1-related diseases. One such protein is Parkinson protein 7, which has been implicated in Parkinson's disease, yet not associated with epilepsy, Alzheimers disease, or autism spectrum disorder. To verify our finding, we provide evidence that the protein expression of Parkinson protein 7, including new protein synthesis, is sensitive to mTORC1 inhibition. Using a mouse model of tuberous sclerosis complex, a disease that displays both epilepsy and autism spectrum disorder phenotypes and has overactive mTORC1 signaling, we show that Parkinson protein 7 protein is elevated in the dendrites and colocalizes with the postsynaptic marker postsynaptic density-95. Our work offers a comprehensive view of mTORC1 and its role in regulating regional protein expression in normal and diseased states. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) 1 is a serine/threonine protein kinase that is highly Author contributions: FN and KRG designed research. FN and SN conducted experiments and analyzed data. SN performed bioinformatics analyses. ES and YM conducted mass spectrometry analyses. GS facilitated mass spectrometry experiments and provided technical advice. GAD and BVZ provided the virus and performed stereotaxic injections. FN, SN, and KRG wrote the manuscript. 1 The abbreviations used are: mTORC1, mechanistic/mammalian target of rapamycin complex 1; AD, Alzheimer's disease; AHA, azidohomoalanine; APP, amyloid precursor protein; ASD, autism spectrum disorder; BONCAT, bioorthogonal noncanonical amino acid

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Section: Brief Rapamycin Exposure Alters Localization and Expression supporting

confidence: 89%

mentioning

confidence: 77%

Analysis of Proteins That Rapidly Change Upon Mechanistic/Mammalian Target of Rapamycin Complex 1 (mTORC1) Repression Identifies Parkinson Protein 7 (PARK7) as a Novel Protein Aberrantly Expressed in Tuberous Sclerosis Complex (TSC)

Niere

Namjoshi²,

Song

et al. 2016

Molecular & Cellular Proteomics

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“…As observed previously (5,25,26), mTORC1 inhibition increased Kv1.1 protein ϳ100% in the primary and ϳ70% in the secondary dendrites (primary dendrite: DMSO, 1.00 Ϯ 0.17; Rapa, 2.04 Ϯ 0.45; secondary dendrite: DMSO, 1.00 Ϯ 0.13; Rapa, 1.72 Ϯ 0.27; Fig. 3, A-D).…”

Section: Nmdar Signaling Activates Mtorc1 In Culturedsupporting

confidence: 85%

Mammalian Target of Rapamycin (mTOR) Tagging Promotes Dendritic Branch Variability through the Capture of Ca2+/Calmodulin-dependent Protein Kinase II α (CaMKIIα) mRNAs by the RNA-binding Protein HuD

Sosanya

Cacheaux

Workman

et al. 2015

Journal of Biological Chemistry

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Background: Memory requires protein synthesis of dendritic CaMKII␣. Results: HuD directs CaMKII␣ expression in a branch-specific manner. mTOR inhibition reduces HuD binding and promotes deadenylation of CaMKII␣ mRNA. Conclusion: mTOR activity tags synapses, allowing HuD to capture CaMKII␣ in a branch-specific manner. Significance: mTOR and HuD provide a molecular model for the synaptic tagging and capture hypothesis.

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“…In the sKA model, K v 4.2 mRNA was reported unchanged in CA1 PCs in the first 24 h but appeared upregulated 12 h later (Francis et al, 1997). In the same model, A-currents of CA1 PCs were decreased but their sensitivity to 50 μM 4-AP and the immunohistochemistry suggested that these currents were rather mediated by K v 1 than K v 4 channels (Sosanya et al, 2014). In contrast to the sPilo rats, tissue from TLE patients with HS displays similar hippocampal K v 4.2 mRNA levels compared to patients without HS, and on the protein level K v 4.2 channels are even elevated, despite the cell loss in the CA1 region (Aronica et al, 2009).…”

Section: Cornu Ammonismentioning

confidence: 95%

“…The Na v 1.2 RNA signal was reduced (Whitaker et al, 2001) while the Ca v 2.1 immuno signal was elevated in CA3 PCs of HS-TLE patients vs. autopsy (Djamshidian et al, 2002). In noHS models, the RNA and immuno intensities of Na v 1.6 channels were found raised in CA3 PCs (Blumenfeld et al, 2009) while those of K v 4.2 and K v 1.1 channels were decreased, respectively (Francis et al, 1997; Sosanya et al, 2014). Because chronic Na v upregulation could lead to depolarization block, functional verification is warranted (Auvin et al, 2008; Cestele et al, 2008).…”

Section: Cornu Ammonismentioning

confidence: 99%

Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential

Wolfart

Laker

2015

Front. Physiol.

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Neurons continuously adapt the expression and functionality of their ion channels. For example, exposed to chronic excitotoxicity, neurons homeostatically downscale their intrinsic excitability. In contrast, the “acquired channelopathy” hypothesis suggests that proepileptic channel characteristics develop during epilepsy. We review cell type-specific channel alterations under different epileptic conditions and discuss the potential of channels that undergo homeostatic adaptations, as targets for antiepileptic drugs (AEDs). Most of the relevant studies have been performed on temporal lobe epilepsy (TLE), a widespread AED-refractory, focal epilepsy. The TLE patients, who undergo epilepsy surgery, frequently display hippocampal sclerosis (HS), which is associated with degeneration of cornu ammonis subfield 1 pyramidal cells (CA1 PCs). Although the resected human tissue offers insights, controlled data largely stem from animal models simulating different aspects of TLE and other epilepsies. Most of the cell type-specific information is available for CA1 PCs and dentate gyrus granule cells (DG GCs). Between these two cell types, a dichotomy can be observed: while DG GCs acquire properties decreasing the intrinsic excitability (in TLE models and patients with HS), CA1 PCs develop channel characteristics increasing intrinsic excitability (in TLE models without HS only). However, thorough examination of data on these and other cell types reveals the coexistence of protective and permissive intrinsic plasticity within neurons. These mechanisms appear differentially regulated, depending on the cell type and seizure condition. Interestingly, the same channel molecules that are upregulated in DG GCs during HS-related TLE, appear as promising targets for future AEDs and gene therapies. Hence, GCs provide an example of homeostatic ion channel adaptation which can serve as a primer when designing novel anti-epileptic strategies.

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Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis

Cited by 42 publications

References 44 publications

Analysis of Proteins That Rapidly Change Upon Mechanistic/Mammalian Target of Rapamycin Complex 1 (mTORC1) Repression Identifies Parkinson Protein 7 (PARK7) as a Novel Protein Aberrantly Expressed in Tuberous Sclerosis Complex (TSC)

Analysis of Proteins That Rapidly Change Upon Mechanistic/Mammalian Target of Rapamycin Complex 1 (mTORC1) Repression Identifies Parkinson Protein 7 (PARK7) as a Novel Protein Aberrantly Expressed in Tuberous Sclerosis Complex (TSC)

Mammalian Target of Rapamycin (mTOR) Tagging Promotes Dendritic Branch Variability through the Capture of Ca2+/Calmodulin-dependent Protein Kinase II α (CaMKIIα) mRNAs by the RNA-binding Protein HuD

Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential

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