Chemoattractant-stimulated granule release from neutrophils, basophils and eosinophils is critical for the innate immune response against infectious bacteria. Interleukin 8 (IL-8) activation of the chemokine receptor CXCRI was found to stimulate rapid formation of beta-arrestin complexes with Hck or c-Fgr. Formation of beta-arrestin-Hck complexes led to Hck activation and trafficking of the complexes to granule-rich regions. Granulocytes expressing a dominant-negative beta-arrestin-mutant did not release granules or activate tyrosine kinases after IL-8 stimulation. Thus, beta-arrestins regulate chemokine-induced granule exocytosis, indicating a broader role for beta-arrestins in the regulation of cellular functions than was previously suspected.
beta-Arrestins are important in chemoattractant receptor-induced granule release, a process that may involve Ral-dependent regulation of the actin cytoskeleton. We have identified the Ral GDP dissociation stimulator (Ral-GDS) as a beta-arrestin-binding protein by yeast two-hybrid screening and co-immunoprecipitation from human polymorphonuclear neutrophilic leukocytes (PMNs). Under basal conditions, Ral-GDS is localized to the cytosol and remains inactive in a complex formed with beta-arrestins. In response to formyl-Met-Leu-Phe (fMLP) receptor stimulation, beta-arrestin Ral-GDS protein complexes dissociate and Ral-GDS translocates with beta-arrestin from the cytosol to the plasma membrane, resulting in the Ras-independent activation of the Ral effector pathway required for cytoskeletal rearrangement. The subsequent re-association of beta-arrestin Ral-GDS complexes is associated with the inactivation of Ral signalling. Thus, beta-arrestins regulate multiple steps in the Ral-dependent processes that result in chemoattractant-induced cytoskeletal reorganization.
The control of neuritic extension and guidance is critical for the development, maturation, and regeneration of functional neuronal circuits. We identified a neuronal 64-85 kDa phosphoprotein, the expression of which in mouse brain is regulated during development, reaching a peak at approximately 5 d postnatal, when maturation of neurons and synaptic connections is highly active. The amino acid sequence of the mouse protein deduced from its cloned cDNA reveals similarities with that of the neuritic outgrowth- and guidance-related product of the unc-33 gene in Caenorhabditis elegans. The regulation of its phosphorylation in response to nerve growth factor, as well as its localization in neurites and growth cones and at the neuromuscular junction, further indicates that Ulip (for Unc-33-like phosphoprotein) is not only a structural but likely is also a functional mammalian homolog of Unc-33, potentially involved in the control of neuritic outgrowth and axonal guidance.
Synapses are well known as the main structures responsible for transmitting information
through the release and recognition of neurotransmitters by pre- and post-synaptic neurons. These
structures are widely formed and eliminated throughout the whole lifespan via processes termed
synaptogenesis and synaptic pruning, respectively. Whilst the first process is needed for ensuring
proper connectivity between brain regions and also with the periphery, the second phenomenon is
important for their refinement by eliminating weaker and unnecessary synapses and, at the same
time, maintaining and favoring the stronger ones, thus ensuring proper synaptic transmission. It is
well-known that synaptic elimination is modulated by neuronal activity. However, only recently the
role of the classical complement cascade in promoting this phenomenon has been demonstrated.
Specifically, microglial cells recognize activated complement component 3 (C3) bound to synapses
targeted for elimination, triggering their engulfment. As this is a highly relevant process for adequate
neuronal functioning, disruptions or exacerbations in synaptic pruning could lead to severe
circuitry alterations that could underlie neuropathological alterations typical of neurological and
neuropsychiatric disorders. In this review, we focus on discussing the possible involvement of excessive
synaptic elimination in Alzheimer’s disease, as it has already been reported dendritic spine
loss in post-synaptic neurons, increased association of complement proteins with its synapses and,
hence, augmented microglia-mediated pruning in animal models of this disorder. In addition, we
briefly discuss how this phenomenon could be related to other neurological disorders, including
multiple sclerosis and schizophrenia.
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