Characterisation of peptide interactions that regulate <scp>PKC</scp>ε activation

Chandrashekaran, Indu R.; Norton, Raymond S.; Schmitz‐Peiffer, Carsten

doi:10.1002/1873-3468.12953

Cited by 3 publications

(2 citation statements)

References 38 publications

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“…Signaling pathways and biological function are regulated by protein–protein interaction, often involving specific protein domains [ 53 , 54 , 55 ]. To examine whether α2 activates the TLR4 signal through its ability to bind TLR4, N2a cells were transfected (or not) with the α2 plasmid and protein extracts (24 h post-transfection) were studied for TLR4/α2 co-precipitation as previously described [ 38 , 39 ] and detailed in Section 2 .…”

Section: Resultsmentioning

confidence: 99%

The GABAA Receptor α2 Subunit Activates a Neuronal TLR4 Signal in the Ventral Tegmental Area that Regulates Alcohol and Nicotine Abuse

et al. 2018

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Alcoholism initiates with episodes of excessive alcohol drinking, known as binge drinking, which is one form of excessive drinking (NIAAA Newsletter, 2004) that is related to impulsivity and anxiety (Ducci et al., 2007; Edenberg et al., 2004) and is also predictive of smoking status. The predisposition of non-alcohol exposed subjects to initiate binge drinking is controlled by neuroimmune signaling that includes an innately activated neuronal Toll-like receptor 4 (TLR4) signal. This signal also regulates cognitive impulsivity, a heritable trait that defines drug abuse initiation. However, the mechanism of signal activation, its function in dopaminergic (TH+) neurons within the reward circuitry implicated in drug-seeking behavior [viz. the ventral tegmental area (VTA)], and its contribution to nicotine co-abuse are still poorly understood. We report that the γ-aminobutyric acidA receptor (GABAAR) α2 subunit activates the TLR4 signal in neurons, culminating in the activation (phosphorylation/nuclear translocation) of cyclic AMP response element binding (CREB) but not NF-kB transcription factors and the upregulation of corticotropin-releasing factor (CRF) and tyrosine hydroxylase (TH). The signal is activated through α2/TLR4 interaction, as evidenced by co-immunoprecipitation, and it is present in the VTA from drug-untreated alcohol-preferring P rats. VTA infusion of neurotropic herpes simplex virus (HSV) vectors for α2 (pHSVsiLA2) or TLR4 (pHSVsiTLR4) but not scrambled (pHSVsiNC) siRNA inhibits signal activation and both binge alcohol drinking and nicotine sensitization, suggesting that the α2-activated TLR4 signal contributes to the regulation of both alcohol and nicotine abuse.

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Section: Resultsmentioning

confidence: 99%

The GABAA Receptor α2 Subunit Activates a Neuronal TLR4 Signal in the Ventral Tegmental Area that Regulates Alcohol and Nicotine Abuse

et al. 2018

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“…An additional study using biophysical surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) indeed confirmed that εV1-2 bound to β -COP and inhibited PKCε binding. In the same study, they also found that ψεRACK did not bind to PKCε, suggesting that their mechanisms of action may be different [139]. The peptides above were developed based on sequence homology between isozymes, in a manner analogous to that depicted in Figure 4.…”

Section: Peptides Derived From Evolutionarily Conserved Sequencesmentioning

confidence: 99%

An Update on Protein Kinases as Therapeutic Targets—Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein–Protein Interactions

Zerihun,

Rubin,

Silnitsky

et al. 2023

IJMS

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Human protein kinases are highly-sought-after drug targets, historically harnessed for treating cancer, cardiovascular disease, and an increasing number of autoimmune and inflammatory conditions. Most current treatments involve small molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP-binding pocket. As a result, these compounds are often poorly selective and highly toxic. Part I of this series reviews the role of PKC isoforms in various human diseases, featuring cancer and cardiovascular disease, as well as translational examples of PKC modulation applied to human health and disease. In the present Part II, we discuss alternative allosteric binding mechanisms for targeting PKC, as well as novel drug platforms, such as modified peptides. A major goal is to design protein kinase modulators with enhanced selectivity and improved pharmacological properties. To this end, we use molecular docking analysis to predict the mechanisms of action for inhibitor–kinase interactions that can facilitate the development of next-generation PKC modulators.

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Endogenous Neurosteroid (3α,5α)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain

Balan

Beattie

O'Buckley

et al. 2019

Sci Rep

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The endogenous neurosteroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) has protective activity in animal models of alcoholism, depression, traumatic brain injury, schizophrenia, multiple sclerosis, and Alzheimer’s disease that is poorly understood. Because these conditions involve proinflammatory signaling through toll-like receptors (TLRs), we examined the effects of 3α,5α-THP, and pregnenolone on TLR4 activation in both the periphery and the central nervous system (CNS). We used monocytes/macrophages (RAW264.7) as a model of peripheral immune signaling and studied innately activated TLR4 in the ventral tegmental area (VTA) of selectively bred alcohol-preferring (P) rats. LPS activated the TLR4 pathway in RAW264.7 cells as evidenced by increased levels of p-TAK1, TRAF6, NF-κB p50, phospho-NF-κB- p65, pCREB, HMGB1, and inflammatory mediators, including MCP-1 and TNFα. Both 3α,5α-THP and pregnenolone (0.5–1.0μM) substantially (~80%) inhibited these effects, indicating pronounced inhibition of TLR4 signaling. The mechanism of inhibition appears to involve blockade of TLR4/MD-2 protein interactions in RAW246.7 cells. In VTA, 3α,5α-THP (15 mg/kg, IP) administration reduced TRAF6 (~20%), CRF (~30%), and MCP-1 (~20%) levels, as well as TLR4 binding to GABAA receptor α2 subunits (~60%) and MyD88 (~40%). The data suggest that inhibition of proinflammatory neuroimmune signaling underlies protective effects of 3α,5α-THP in immune cells and brain, apparently involving blocking of protein-protein interactions that initiate TLR4-dependent signaling. Inhibition of pro-inflammatory TLR4 activation represents a new mechanism of 3α,5α-THP action in the periphery and the brain.

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Characterisation of peptide interactions that regulate PKCε activation

Cited by 3 publications

References 38 publications

The GABAA Receptor α2 Subunit Activates a Neuronal TLR4 Signal in the Ventral Tegmental Area that Regulates Alcohol and Nicotine Abuse

The GABAA Receptor α2 Subunit Activates a Neuronal TLR4 Signal in the Ventral Tegmental Area that Regulates Alcohol and Nicotine Abuse

An Update on Protein Kinases as Therapeutic Targets—Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein–Protein Interactions

Endogenous Neurosteroid (3α,5α)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain

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