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PubMed2006

Stabilization of yeast hexokinase A by polyol osmolytes: correlation with the physicochemical properties of aqueous solutions.

Osmolytes of the polyol series are known to accumulate in biological systems under stress and stabilize the structures of a wide variety of proteins. While increased surface tension of aqueous solutions has been considered an important factor in protein stabilization effect, glycerol is an exception, lowering the surface tension of water. To clarify this anomalous effect, the effect of a series of polyols on the thermal stability of a highly thermolabile two domain protein yeast hexokinase A has been investigated by differential scanning calorimetry and by monitoring loss in the biological activity of the enzyme as a function of time. A larger increase in the T(m) of domain 1 compared with that of domain 2, varying linearly with the number of hydroxyl groups in polyols, has been observed, sorbitol being the best stabilizer against both thermal as well as urea denaturation. Polyols help retain the activity of the enzyme considerably and a good correlation of the increase in T(m) (DeltaT(m)) and the retention of activity with the increase in the surface tension of polyol solutions, except glycerol, which breaks this trend, has been observed. However, the DeltaT(m) values show a linear correlation with apparent molal heat capacity and volume of aqueous polyol solutions including glycerol. These results suggest that while bulk solution properties contribute significantly to protein stabilization, interfacial properties are not always a good indicator of the stabilizing effect. A subtle balance of various weak binding and exclusion effects of the osmolytes mediated by water further regulates the stabilizing effect. Understanding these aspects is critical in the rational design of stable protein formulations.

Circular Dichroism↗
PubMed2006

Prediction of protein mutant stability using classification and regression tool.

Prediction of protein stability upon amino acid substitutions is an important problem in molecular biology and the solving of which would help for designing stable mutants. In this work, we have analyzed the stability of protein mutants using two different datasets of 1396 and 2204 mutants obtained from ProTherm database, respectively for free energy change due to thermal (DeltaDeltaG) and denaturant denaturations (DeltaDeltaG(H(2)O)). We have used a set of 48 physical, chemical energetic and conformational properties of amino acid residues and computed the difference of amino acid properties for each mutant in both sets of data. These differences in amino acid properties have been related to protein stability (DeltaDeltaG and DeltaDeltaG(H(2)O)) and are used to train with classification and regression tool for predicting the stability of protein mutants. Further, we have tested the method with 4 fold, 5 fold and 10 fold cross validation procedures. We found that the physical properties, shape and flexibility are important determinants of protein stability. The classification of mutants based on secondary structure (helix, strand, turn and coil) and solvent accessibility (buried, partially buried, partially exposed and exposed) distinguished the stabilizing/destabilizing mutants at an average accuracy of 81% and 80%, respectively for DeltaDeltaG and DeltaDeltaG(H(2)O). The correlation between the experimental and predicted stability change is 0.61 for DeltaDeltaG and 0.44 for DeltaDeltaG(H(2)O). Further, the free energy change due to the replacement of amino acid residue has been predicted within an average error of 1.08 kcal/mol and 1.37 kcal/mol for thermal and chemical denaturation, respectively. The relative importance of secondary structure and solvent accessibility, and the influence of the dataset on prediction of protein mutant stability have been discussed.

Amino Acid Substitution↗
PubMed2005

Lithium differs from anticonvulsant mood stabilizers in prefrontal cortical and accumbal dopamine release: role of 5-HT(1A) receptor agonism.

Anticonvulsant mood stabilizers, e.g., valproic acid and carbamazepine, and atypical antipsychotic drugs (APDs), e.g., clozapine, quetiapine, olanzapine, risperidone, and ziprasidone, have been reported to preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC), an effect partially or fully inhibited by WAY100635, a selective 5-HT(1A) antagonist. These atypical APDs have themselves been reported to be effective mood stabilizers, although the importance of increased cortical DA release to mood stabilization has not been established. The purpose of the present study was to determine whether zonisamide, another anticonvulsant mood stabilizer, as well as lithium, a mood stabilizer without anticonvulsant properties, also increases prefrontal cortical DA release and, if so, whether this release is also inhibited by 5-HT(1A) antagonism. As with valproic acid and carbamazepine, zonisamide (12.5 and 25 mg/kg) increased DA release in the mPFC, but not the NAC, an increase abolished by WAY100635 (0.2 mg/kg). However, lithium (100 and 250 mg/kg) decreased DA release in the NAC, an effect also attenuated by WAY100635 (0.2 mg/kg). Lithium itself had no effect in the mPFC but the combination of WAY100635 (0.2 mg/kg) and lithium (100 and 250 mg/kg) markedly increased DA release in the mPFC. Furthermore, M100907 (0.1 mg/kg), a selective 5-HT(2A) antagonist, abolished this increase in DA release in the mPFC. These results indicate that not all mood-stabilizing agents but only those, which have anticonvulsant mood-stabilizing properties, increase DA release in the cortex, and that the effect is dependent upon 5-HT(1A) receptor stimulation. However, the combination of lithium and 5-HT(1A) blockade may result in excessive 5-HT(2A) receptor stimulation, relative to 5-HT(1A) receptor stimulation, both of which can increase prefrontal cortical DA release.

Analysis of Variance↗
PubMed2006

Within-subject reliability and inter-session stability of EEG power and coherent activity in women evaluated monthly over nine months.

OBJECTIVE: Quantitative EEG parameters during resting conditions are used as baseline in research on cognition and in serial-EEG recordings. Despite its increasing use in cognitive research and the numerous evidences of the existence of sex differences in EEG, EEG stability has been mainly investigated in men. Particularly, studies on stability of coherent activity are scarce. The aim of this study was to investigate within-subject reliability and inter-session stability of resting EEG over a nine-month period in women. METHODS: Within-subject reliability and inter-session stability were analyzed for absolute power and inter- and intrahemispheric coherent activity at central and posterior regions, once a month, in resting conditions, with eyes open and closed. RESULTS: Within-subject reliability was very high (r>0.89) for all subjects and EEG parameters. Inter-session stability was higher with eyes closed and for interhemispheric coherent activity, and poorer with eyes open especially in the alpha band. CONCLUSIONS: Present results indicate high reliability of the pattern of power and coherent activity of each individual woman during rest, and group stability of EEG activity with eyes closed at least over a nine-month period. SIGNIFICANCE: These results provide information on EEG stability in women over a long period.

Adolescent↗
PubMed2004

Local factors determine the stabilization of monocular ambiguous and binocular rivalry stimuli.

Perceptual alternation in viewing bistable stimuli can be slowed or halted if the stimuli are presented intermittently. Memory of the recent perceptual experience has been proposed to explain this stabilization effect. But the nature of this "perceptual memory" remains unclear. By using a bistable rotating cylinder and two dichoptically presented orthogonal gratings, we explored the features that are important for the stabilization by changing a particular feature of the stimuli between alternate presentations. For the rotating cylinder, changing its color, rotating speed, size, or its stereo depth had no or minimal effect on the stabilization of its perceived rotation direction. For binocular rivalry, when the two gratings were matched in strength and then swapped between the two eyes synchronously with the intermittent presentation, the percepts were usually stabilized to one eye. In both cases, perceptual stabilization occurred only if the stimuli were presented to the same retinal location. These results suggest that the stabilization of monocular bistable stimuli is likely due to the removal of local adaptation, insensitive to the features that define the object identity. For binocular rivalry, preservation of the direction of interocular suppression rather than memory of the stimulus identity accounts for the stabilization effect.

Adult↗
PubMed2005

Rapid, Wnt-induced changes in GSK3beta associations that regulate beta-catenin stabilization are mediated by Galpha proteins.

BACKGROUND: In the absence of Wnt stimulation, the transcriptional cofactor beta-catenin is destabilized via phosphorylation by protein kinase GSK3beta in complex with Axin family members. In the "canonical" Wnt signaling pathway, Disheveled (Dvl) is required to functionally inhibit the activity of the GSK3beta/Axin complex and thereby stabilize beta-catenin. Yet, the mechanisms that underlie Wnt regulation of GSK3 and stabilization of beta-catenin are still not fully appreciated. RESULTS: Here, we examine time-dependent changes in protein-protein interactions that occur in response to Wnt treatment. We show that GSK3beta/Axin complexes are rapidly (t1/2 < 3 min) disrupted upon Wnt stimulation and that changes in GSK3beta/Axin association substantially precede both beta-catenin stabilization and Axin degradation. We further demonstrate that depletion of Galpha(o) or Galpha(q) will inhibit, respectively, the Wnt-induced disruption of GSK3beta/Axin2 and GSK3beta/Axin complexes and diminish Wnt stabilization of beta-catenin. We also show that direct activation of G proteins in vivo with GTPgammaS in the absence of exogenous Wnt will disrupt GSK3beta/Axin2 complexes and stabilize beta-catenin. Finally, we demonstrate an association of Galpha(o) with Fz that is also very rapidly (t1/2 < 1 min) perturbed upon Wnt-3a stimulation and that the Wnt-dependent effects on both GSK3beta/Axin2 and Galpha(o)/Fz are pertussis-toxin sensitive. Collectively, these data implicate a role for G proteins in the regulation of Wnt-mediated protein-protein interactions and signaling to beta-catenin. CONCLUSIONS: We conclude that rapid disruption of GSK3beta/Axin interactions in response to Wnt leads to the initial stabilization of beta-catenin and that Galpha(o) and Galpha(q) signaling contributes to Wnt-mediated GSK3beta/Axin disruption and the ultimate stabilization of beta-catenin.

Animals↗
PubMed2006

Investigation of nanocapsules stabilization by amorphous excipients during freeze-drying and storage.

Freeze-drying was recently applied to improve the long-term storage stability of nanoparticles. Nanocapsules have a thin polymeric envelope that may not withstand the stresses of such process. So, cryoprotectants and lyoprotectants are usually added to the formulation to protect these vectors during freezing and desiccation steps. The aim of this paper was to investigate the importance of the vitrification of cryoprotectants on the stabilization of nanocapsules during freezing, desiccation, and storage steps. Furthermore, the effect of stabilizer crystallization on the conservation of nanocapsules properties was studied. Finally, the effect of temperature storage and relative humidity on the stability of nanocapsules was tested through an accelerated stability study. Results indicate that nanocapsules stabilization during the different steps of freeze-drying requires their dispersion within a vitrified matrix of amorphous excipient to protect them against the stress of freezing and dehydration. The crystallization of this stabilizer during the freezing, the desiccation or the storage steps can destabilize these fragile particles. Electron spectroscopy for chemical analysis revealed the adsorption of nanocapsules at the interface ice/liquid during the freezing step. Such adsorption must be avoided in the case of freeze-drying of immuno-nanoparticles to preserve the native structure of proteins attached to their surface.

Drug Storage↗
PubMed2006

Changes in postural stability with fatigue of lower extremity frontal and sagittal plane movers.

The purpose of this study was to quantify changes in postural stability with fatigue of the frontal and sagittal movers of the lower extremities. There were four test sessions, with a randomized order assigned according to the muscles tested and the plane of motion. Subjects were 20 healthy men (age: 22.6+/-2.4 years, height: 173.7+/-3.6 cm, weight: 63.3+/-7.9 kg). During each session, one set of muscle groups was fatigued using isokinetic contractions: ankle plantar/dorsi flexors, ankle evertor/invertors, hip flexor/extensors or hip abductor/adductors. The Biodex Stability System was used to assess anterior/posterior and medial/lateral stability before and after muscle fatigue. Repeated measures ANOVAs revealed that fatigue was associated with a significant increase in all stability indices. Fatigue of the hip movers, whether in the frontal or sagittal planes, led to greater increments in stability indices than fatigue of the ankle musculature. Fatigue of the frontal movers resulted in greater increases in the medial/lateral stability index compared to fatigue of the sagittal movers. In conclusion, fatigue of proximal lower extremity muscles affects postural stability and fatigue of the frontal movers is associated with postural instability in the frontal plane.

Adult↗
PubMed2005

Stabilizer choice for rapid dissolving high potency itraconazole particles formed by evaporative precipitation into aqueous solution.

The objective of this study was to investigate the influence of stabilizer type on the physicochemical properties, including dissolution, of ultra-high potency powders containing itraconazole (ITZ) formed by evaporative precipitation into aqueous solution (EPAS). ITZ was dissolved in dichloromethane, which was then atomized through a heated coil at 80 degrees C into an aqueous solution over precise periods of time. Stabilizers were present in either the aqueous, organic or both phases. The dispersions were centrifuged and the supernatant was removed. Three hydrophilic stabilizers were investigated, including polysorbate 80, polyvinyl pyrrolidone and poloxamer 407. Rapid dissolving ultra-high potency of ITZ powders was successfully produced. Greater than 80% of ITZ was dissolved in 5 min compared to only 13% of ITZ bulk powders. The resulting stabilizer-coated drug particles had high drug-to-stabilizer ratios greater than 12, corresponding to potencies (wt drug/wt drug+wt surfactant) as high as 93%. An increase in dissolution rate was correlated with the amount of stabilizer adsorbed and the wettability. The combination of polysorbate 80 and poloxamer 407 present in the aqueous and organic phases, respectively, was superior in achieving high wetting and rapid dissolving ITZ powders. The ability to control the adsorption behavior of stabilizers by using synergistic combinations affords the opportunity to achieve high dissolution rates with higher potencies compared to previously reported values.

Adsorption↗
PubMed2005

A pilot study of freeze drying of poly(epsilon-caprolactone) nanocapsules stabilized by poly(vinyl alcohol): formulation and process optimization.

A common limitation of using polymeric nanoparticles in aqueous suspension is due to their poor chemical and physical stability when conserved for a long time. Therefore, freeze drying of these colloidal systems is an alternative method to achieve long-term stability. Nanocapsules have thin and fragile shell structure, which may not resist to the stress of such process. The aim of this study is to investigate the formulation and process parameters in order to ensure the stability of polycaprolactone nanocapsules (PCL NC) by freeze drying. In this paper, we studied the freeze drying of PCL NC prepared by the emulsion-diffusion method and stabilized by poly(vinyl alcohol) (PVA). Different parameters have been tested throughout the freeze-thawing study including PVA and PCL concentration, cooling rate, cryoprotectant concentrations, nature of encapsulated oil and NC purification. On the other hand, nanocapsules have been freeze dried both before and after purification. Freeze dried purified PCL NC were characterized by particle size measurement, collapse temperature, T'g determination, scanning electron microscope observation, environmental scanning electron microscope imaging and residual humidity quantification. Finally, the effect of annealing on the NC stability and the sublimation rate has been well explored. The results suggest that PCL NC could be freeze dried without a cryoprotectant if the concentration of PVA stabilizer is sufficient (5%), while for the purified NC the addition of 5% of cryoprotectant seems to be necessary to ensure the stability of NC. The type of cryoprotectants had practically negligible effects on the size and the rehydration of freeze dried nanocapsules. The annealing process could accelerate the sublimation with the conservation of nanocapsules size.

Capsules↗
PubMed2006

Model and in vivo studies on human trunk load partitioning and stability in isometric forward flexions.

To resolve the trunk redundancy to determine muscle forces, spinal loads, and stability margin in isometric forward flexion tasks, combined in vivo-numerical model studies was undertaken. It was hypothesized that the passive resistance of both the ligamentous spine and the trunk musculature plays a crucial role in equilibrium and stability of the system. Fifteen healthy males performed free isometric trunk flexions of approximately 40 degrees and approximately 65 degrees +/- loads in hands while kinematics by skin markers and EMG activity of trunk muscles by surface electrodes were measured. A novel kinematics-based approach along with a nonlinear finite element model were iteratively used to calculate muscle forces and internal loads under prescribed measured postures and loads considered in vivo. Stability margin was investigated using nonlinear, linear buckling, and perturbation analyses under various postures, loads and alterations in ligamentous stiffness. Flexion postures significantly increased activity in extensor muscles when compared with standing postures while no significant change was detected in between flexed postures. Compression at the L5-S1 substantially increased from 570 and 771 N in upright posture, respectively, for +/-180 N, to 1912 and 3308 N at approximately 40 degrees flexion, and furthermore to 2332 and 3850 N at approximately 65 degrees flexion. Passive ligamentous/muscle components resisted up to 77% of the net moment. In flexion postures, the spinal stability substantially improved due both to greater passive stiffness and extensor muscle activities so that, under 180 N, no muscle stiffness was required to maintain stability. The co-activity of abdominal muscles and the muscle stiffness were of lesser concern to maintain stability in forward flexion tasks as compared with upright tasks. An injury to the passive system, on one hand, required a substantial compensatory increase in active muscle forces which further increased passive loads and, hence, the risk of injury and fatigue. On the other hand, it deteriorated the system stability which in turn could require greater additional muscle activation. This chain of events would place the entire trunk active-passive system at higher risks of injury, fatigue and instability.

Abdomen↗
PubMed2005

Primary stability of an anatomical cementless hip stem: a statistical analysis.

The primary stability that the surgeon can achieve during surgery is a determinant of the clinical success of cementless implants. Thus, estimating what level of primary stability can be obtained with a new design is an important aspect of pre-clinical evaluation. The primary stability of a cementless hip stem is not only affected by the implant design, but also by other factors such as the mechanical quality of the host bone, the presence of gaps around the bone-implant interface, the body weight of the patient, and the size of the implant. Even the most extensive experimental study can only explore a small sub-set of all possible combinations found in vivo. To overcome this limitation, we propose a combination of experimental and numerical methods. The primary stability of a cementless anatomical stem is assessed in vitro. A finite element model is developed to accurately replicate the same experiment. The model is then parameterised over the various factors that affect the primary stability, and used in a Monte Carlo scheme to assess the primary stability over a simulated population. In this study, the method was used to investigate the mechanical stability of an anatomical cementless stem over more than 1000 simulated cases. Twenty cases were found macroscopically unstable, due to a combination of unfavourable conditions. The rest of the Monte Carlo sample showed on average a peak micromotion under stair climbing loading of 206 +/- 159 microm. The proposed method can be used to evaluate new designs in conditions more representative of the variability in clinical practice.

Arthroplasty, Replacement, Hip↗
PubMed2004

Heavy metal stabilization in municipal solid waste incineration flyash using heavy metal chelating agents.

Heavy metal chemical stabilization with synthesized heavy metal chelating agent was assessed for flyash from municipal solid waste incinerator. Flyash can contain heavy metals (e.g. Pb, Cd) which can leach. A new kind of heavy metal chelating agent showed more attractive competition than inorganic chemicals in stabilizing flyash. The synthesizing method of this kind of heavy metal chelating agent was explained in this paper, and the technology process and treatment efficiency of the chelating agent in treating flyash were experimentally studied, which was compared with the results of inorganic chemical agents such as sodium sulfide and lime. The heavy metals in flyash were stabilized more effectively by using heavy metal chelating agents than by using sodium sulfide and lime, furthermore, the stabilized products using the chelating agents can meet the landfill disposal controlling standards for heavy metal waste. pH-dependent leaching experiment showed the stabilized flyash by treatment with heavy metal chelating agent could keep long-term stabilization within a broad range of pH value. Thus, the risk of secondary pollution for the stabilized products was reduced dramatically when the environment condition changes during its disposal period.

Carbon↗
PubMed2004

Relation between protein stability, evolution and structure, as probed by carboxylic acid mutations.

Native proteins are marginally stable. Low thermodynamic stability may actually be advantageous, although the accumulation of neutral, destabilizing mutations may have also contributed to it. In any case, once marginal stability has been reached, it appears plausible that mutations at non-constrained positions become fixed in the course of evolution (due to random drift) with frequencies that roughly reflect the mutation effects on stability ("pseudo-equilibrium hypothesis"). We have found that all glutamate-->aspartate mutations in wild-type Escherichia coli thioredoxin are destabilizing, as well as most of the aspartate-->glutamate mutations. Furthermore, the effect of these mutations on thioredoxin thermodynamic stability shows a robust correlation with the frequencies of occurrence of the involved residues in several-hundred sequence alignments derived from a BLAST search. These results provide direct and quantitative experimental evidence for the pseudo-equilibrium hypothesis and should have general consequences for the interpretation of mutation effects on protein stability, as they suggest that residue environments in proteins may be optimized for stabilizing interactions to a remarkable degree of specificity. We also provide evidence that such stabilizing interactions may be detected in sequence alignments, and briefly discuss the implications of this possibility for the derivation of structural information (on native and denatured states) from comparative sequence analyses.

Aspartic Acid↗
PubMed2005

Effects of pH, salt, and macromolecular crowding on the stability of FK506-binding protein: an integrated experimental and theoretical study.

Environmental variables can exert significant influences on the folding stability of a protein, and elucidating these influences provides insight on the determinants of protein stability. Here, experimental data on the stability of FKBP12 are reported for the effects of three environmental variables: pH, salt, and macromolecular crowding. In the pH range of 5-9, contribution to the pH dependence of the unfolding free energy from residual charge-charge interactions in the unfolded state was found to be negligible. The negligible contribution was attributed to the lack of sequentially nearest neighboring charged residues around groups that titrate in the pH range. KCl lowered the stability of FKBP12 and the E31Q/D32N double mutant at small salt concentrations but raised stability after approximately 0.5 M salt. Such a turnover behavior was accounted for by the balance of two opposing types of protein-salt interactions: the Debye-Hückel type, modeling the response of the ions to protein charges, favors the unfolded state while the Kirkwood type, accounting for the disadvantage of the ions moving toward the low-dielectric protein cavity from the bulk solvent, disfavors the unfolded state. Ficoll 70 as a crowding agent was found to have a modest effect on protein stability, in qualitative agreement with a simple model suggesting that the folded and unfolded states are nearly equally adversely affected by macromolecular crowding. For any environmental variable, it is the balance of its effects on the folded and unfolded states that determines the outcome on the folding stability.

Ficoll↗
PubMed2005

Stabilization of the ribosomal protein S6 by trehalose is counterbalanced by the formation of a putative off-pathway species.

The effect of trehalose on folding and stability of the small ribosomal protein S6 was studied. Non-disruptive point mutations distributed along the protein structure were analyzed to characterize the stabilizing effect of trehalose and map the folding pathway of S6. On average, the stability of the wild-type and S6 mutants increases by 3 kcal/mol M trehalose. Despite the non-specific thermodynamic stabilization mechanism, trehalose particularly stabilizes the less destabilized mutants. Folding/unfolding kinetics shows clearly that trehalose induces the collapse of the unfolded state to an off-pathway intermediate with non-native diffuse contacts. This state is similar to the collapsed state induced by high concentrations of stabilizing salts, as previously reported. Although it leads to the accumulation of this off-pathway intermediate, trehalose does not change the compactness of the transition state ensemble. Furthermore, the productive folding pathway of S6 is not affected by trehalose as shown by a Phi-value analysis. The unfolded state ensemble of S6 should be more compact in the presence of trehalose and therefore destabilized due to decreased conformational entropy. Increased compaction of the unfolded state ensemble might also occur for more stable mutants of S6, thus explaining the synergistic effect of trehalose and point mutations on protein stabilization.

Circular Dichroism↗
PubMed2006

Enhancing the stability and folding rate of a repeat protein through the addition of consensus repeats.

Repeat proteins are constructed from a linear array of modular units, giving rise to an overall topology lacking long-range interactions. This suggests that stabilizing repeat modules based on consensus information might be added to a repeat protein domain, allowing it to be extended without altering its overall topology. Here we add consensus modules the ankyrin repeat domain from the Drosophila Notch receptor to investigate the structural tolerance to these modules, the relative thermodynamic stability of these hybrid proteins, and how alterations in the energy landscape influence folding kinetics. Insertions of consensus modules between repeats five and six of the Notch ankyrin domain have little effect on the far and near-UV CD spectra, indicating that neither secondary nor tertiary structure is dramatically altered. Furthermore, stable structure is maintained at increased denaturant concentrations in the polypeptides containing the consensus repeats, indicating that the consensus modules are capable of stabilizing much of the domain. However, insertion of the consensus repeats appears to disrupt cooperativity, producing a two-stage (three-state) unfolding transition in which the C-terminal repeats unfold at moderate urea concentrations. Removing the C-terminal repeats (Notch ankyrin repeats six and seven) restores equilibrium two-state folding and demonstrates that the high stability of the consensus repeats is propagated into the N-terminal, naturally occurring Notch ankyrin repeats. This stability increase greatly increases the folding rate, and suggests that the transition state ensemble may be repositioned in the chimeric consensus-stabilized proteins in response to local stability.

Amino Acid Sequence↗
PubMed2005

LIM Kinase1 controls synaptic stability downstream of the type II BMP receptor.

Here, we demonstrate that the BMP receptor Wishful Thinking (Wit) is required for synapse stabilization. In the absence of BMP signaling, synapse disassembly and retraction ensue. Remarkably, downstream Smad-mediated signaling cannot fully account for the stabilizing activity of the BMP receptor. We identify LIM Kinase1 (DLIMK1)-dependent signaling as a second, parallel pathway that confers the added synapse-stabilizing activity of the BMP receptor. We show that DLIMK1 binds a region of the Wit receptor that is necessary for synaptic stability but is dispensable for Smad-mediated synaptic growth. A genetic analysis demonstrates that DLIMK1 is necessary, presynaptically, for synapse stabilization, but is not necessary for normal synaptic growth or function. Furthermore, presynaptic expression of DLIMK1 in a wit or mad mutant significantly rescues synaptic stability, growth, and function. DLIMK1 localizes near synaptic microtubules and functions independently of ADF/cofilin, highlighting a novel requirement for DLIMK1 during synapse stabilization rather than actin-dependent axon outgrowth.

Actin Depolymerizing Factors↗