How does the corpus callosum mediate interhemispheric transfer? A review

The corpus callosum is the largest white matter structure in the human brain, connecting cortical regions of both hemispheres. Complete and partial callosotomies or callosal lesion studies have granted more insight into the function of the corpus callosum, namely the facilitation of communication between the cerebral hemispheres. How the corpus callosum mediates this information transfer is still a topic of debate. Some pose that the corpus callosum maintains independent processing between the two hemispheres, whereas others say that the corpus callosum shares information between hemispheres. These theories of inhibition and excitation are further explored by reviewing recent behavioural studies and morphological findings to gain more information about callosal function. Additional information regarding callosal function in relation to altered morphology and dysfunction in disorders is reviewed to add to the discussion of callosal involvement in interhemispheric transfer. Both the excitatory and inhibitory theories seem likely candidates to describe callosal function, however evidence also exists for both functions within the same corpus callosum. For future research it would be beneficial to investigate the functional role of the callosal sub regions to get a better understanding of function and use more appropriate experimental methods to determine functional connectivity when looking at interhemispheric transfer.     

A Meta-Analysis Comparing Open-Label versus Placebo-Controlled Clinical Trials for Aripiprazole Augmentation in the Treatment of Major Depressive Disorder: Lessons and Promises

Objective

The present study is to provide whether open-label studies (OLS) may properly foresee the efficacy of randomized, placebo-controlled trials (RCTs) using OLSs and RCTs data for aripiprazole in the treatment of MDD, with the use of meta-analysis approach.

Methods

A search of the studies used the key terms "depression and aripiprazole" from the databases of PubMed/PsychInfo from Jan 2005 through July 2013. The data were selected and verified for publication in English-based peer-reviewed journals based on rigorous inclusion criteria. Extracted data were delivered into and run by the Comprehensive Meta Analysis program v2.

Results

The pooled SMDs for the primary efficacy measure was statistically significant, pointing out the significant reduction of depressive symptoms after aripiprazole augmentation (AA) to current antidepressant treatment in OLSs (pooled SMD=-2.114, z=-9.625, p<0.001); similar results were also found in RCTs (pooled SMD=-2.202, z=-6.862, p<0.001). The meta-regression analysis revealed no influence of the study design for treatment outcome.

Conclusion

There was no difference in the treatment effects of aripiprazole as an augmentation therapy in both OLSs and RCTs, indicating that open-label design may be a potentially useful predictor for treatment outcomes of controlled-clinical trials. The proper conduction of OLSs may provide informative, useful and preliminary clinical data and factors to be involved in controlled-clinical trials, by which we may have better understanding on the role of AA (e.g., dosing issues, proper duration of treatment, specific population for AA) implicated in the treatment of MDD in clinical practice.     

Scaffolding mechanism of arrestin-2 in the cRaf/MEK1/ERK signaling cascade

Arrestins were initially identified for their role in homologous desensitization and internalization of G protein–coupled receptors. Receptor-bound arrestins also initiate signaling by interacting with other signaling proteins. Arrestins scaffold MAPK signaling cascades, MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK. In particular, arrestins facilitate ERK1/2 activation by scaffolding ERK1/2 (MAPK), MEK1 (MAP2K), and Raf (MAPK3). However, the structural mechanism underlying this scaffolding remains unknown. Here, we investigated the mechanism of arrestin-2 scaffolding of cRaf, MEK1, and ERK2 using hydrogen/deuterium exchange–mass spectrometry, tryptophan-induced bimane fluorescence quenching, and NMR. We found that basal and active arrestin-2 interacted with cRaf, while only active arrestin-2 interacted with MEK1 and ERK2. The ATP binding status of MEK1 or ERK2 affected arrestin-2 binding; ATP-bound MEK1 interacted with arrestin-2, whereas only empty ERK2 bound arrestin-2. Analysis of the binding interfaces suggested that the relative positions of cRaf, MEK1, and ERK2 on arrestin-2 likely facilitate sequential phosphorylation in the signal transduction cascade.

The mitogen-activated protein kinase (MAPK) signaling cascade is an intracellular signaling pathway that is activated by diverse external stresses and regulates various cellular functions such as differentiation and proliferation (1). MAPK activation cascades consist of three components: MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK. MAP3K phosphorylates and activates MAP2K, which in turn phosphorylates and activates MAPK (1, 2). In mammals, there are four distinct MAPK groups, ERKs (ERK1 and 2), JNKs (JNK1, 2, and 3), p38 (p38α through δ), and ERK5, each of which has its own upstream MAP3Ks and MAP2Ks (2, 3).A long-standing question in biochemistry is how diverse input signals can generate a specific MAPK signaling cascade. In other words, it is unknown how MAPK signaling modules dynamically interact in a spatiotemporal manner. To accomplish signaling fidelity, scaffolding proteins play an important role in colocalizing MAPK signaling modules. MAPK scaffolding proteins facilitate activation, regulate subcellular localization, and/or modulate the negative feedback of a specific MAPK signaling, which helps to organize a specific MAPK module to link the input signaling to proper biological outcomes (4, 5). Owing to the diverse roles of MAPK scaffolding proteins, they have been considered as potential therapeutic targets (6, 7).In mammals, a number of MAPK scaffolding proteins, including JIP, KSR, paxillin, MORG1, JSAP1, and arrestins, have been identified (8, 9). The functional role of MAPK scaffolding and the molecular and structural mechanisms of how the MAPK scaffolding proteins interact with MAPK signaling components vary depending on the scaffolding proteins (4). Therefore, it is important to study the details of the scaffolding mechanism of each MAPK scaffolding protein to gain a better understanding of the MAPK signaling mechanism and to precisely regulate a specific MAPK signaling pathway for therapeutic purposes.Arrestins were first discovered as proteins that play a key role in homologous desensitization and internalization of G protein–coupled receptors (GPCRs) (10). Four arrestins (arrestin-1 through -4) have been identified in humans: arrestin-1 and -4 (visual and cone arrestins, respectively) are expressed exclusively in the visual system, whereas arrestin-2 and -3 (also known as β-arrestin1 and 2, respectively) are ubiquitously expressed (10). Agonist-activated GPCRs, after coupling with G proteins, are phosphorylated by GPCR kinases. Arrestins bind active phosphorylated GPCRs, precluding receptor coupling to G proteins and facilitating receptor internalization (10, 11). In GPCR internalization, arrestins act as scaffolding proteins, linking the receptor with components of internalization machinery, such as clathrin and AP-2 (11–15). Arrestins have also been reported to interact with numerous signaling proteins, including MAPKs, and perform multiple functions (16, 17). The interaction with these signaling proteins occurs either in the basal or GPCR-induced active state of arrestins (11, 15, 18).Arrestins are the only known scaffolding proteins for MAPKs that are regulated by GPCRs. The interaction between MAPKs and arrestins has been extensively studied (11, 15, 19–21). Arrestins regulate GPCR-mediated ERK1/2 activation by scaffolding cRaf-1, MEK1, and ERK1/2 (22, 23) and regulate GPCR-dependent or -independent JNK3 signaling by scaffolding ASK1, MKK4/7, and JNK3 (24–26). Although the cellular and physiological effects of arrestins in MAPK signaling cascades have been studied extensively, the structural mechanisms governing arrestin/MAPK interactions have not been fully elucidated. Only a few studies have suggested a scaffolding mechanism of arrestins for ERK1/2 and JNK3 signaling components. A molecular simulation approach has suggested the binding interfaces of GPCR, arrestin-2, cSrc, cRaf, MEK1, and ERK1 (27), and mutation or truncation studies have investigated the interaction sites between arrestin and ERK1/2 signaling components (22, 28). Recent studies suggested an arrestin-3-mediated scaffolding and signal amplification mechanism of the JNK3 cascade (26, 29).Here, we studied the interaction of ERK1/2 signaling cascade components (cRaf, MEK1, and ERK2) with arrestin-2 using a combination of hydrogen/deuterium exchange–mass spectrometry (HDX-MS), Trp-induced bimane fluorescence quenching, and NMR spectroscopy. HDX-MS measures the exchange rate between the hydrogen atoms of amides in the protein backbone and the deuterium atoms in the solvent, which can provide an insight into protein–protein binding interfaces (30). NMR and Trp-induced bimane fluorescence quenching enable the detailed mapping of interaction interfaces within proteins (29, 31).