Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present minireview describes experiments carried out, in short-term crush-operated rat nerves, using immunofluorescence and cytofluorimetric scanning techniques to study endogenous substances in anterograde and retrograde fast axonal transport. Vesicle membrane components p38 (synaptophysin) and SV2 are accumulating on both sides of a crush, but a larger proportion of p38 (about 3/4) than of SV2 (about 1/2) is recycling toward the cell body, compared to the amount carried with anterograde transport. Matrix peptides, such as CGRP, ChRA, VIP, and DBH are recycling to a minor degree, although only 10-20% of surface-associated molecules, such as synapsins and kinesin, appear to recycle. The described methodological approach to study the composition of organelles in fast axonal transport, anterograde as compared to retrograde, is shown to be useful for investigating neurobiological processes. We make use of the "in vivo chromatography" process that the fast axonal transport system constitutes. Only substances that are in some way either stored in, or associated with, transported organelles can be clearly observed to accumulate relative to the crush region. Emphasis in this paper was given to the synapsins, because of diverging results published concerning the degree of affiliation with various neuronal organelles. Our previously published results have indicated that in the living axons the SYN I is affiliated with mainly anterogradely fast transported organelles. Therefore, some preliminary, previously unpublished results on the accumulations of the four different synapsins (SYN Ia, SYN Ib, SYN IIa, and SYN IIb), using antisera specific for each of the four members of the synapsin family, are described. It was found that SYN Ib clearly has a stronger affiliation to anterogradely transported organelles than SYN Ia, and that both SYN IIa and SYN IIb are bound to some degree to transported organelles.
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PMID:Organelles in fast axonal transport. What molecules do they carry in anterograde vs retrograde directions, as observed in mammalian systems? 128 29

The purely GABAergic nature of spontaneous synaptic activity in cultures from the neonatal rat superior colliculus (SC) is of great advantage in investigations aimed at characterizing presynaptic factors regulating GABAergic synaptic transmission. Using SC-derived cultures it was confirmed that excitatory amino acids (EAA) can induce a marked increase in the frequency of spontaneous synaptic Cl- currents (ICl(GABA)SYN). However, this tetrodotoxin-resistant facilitation of Ca2(+)-dependent GABA release required application of EEA to several neurons (multiple cell superfusion). In contrast, no frequency increase of Icl(GABA)SYN was seen with restricted access of EAA to only one neuron and the presynaptic axonal terminals (single cell superfusion). It is therefore concluded that the strong facilitatory effect of glutamate (Glu) and kainate (KA) on GABAergic synaptic activity, as observed under the condition of multiple cell superfusion, is mediated via somatodendritic excitatory amino acid receptors (EAARs).
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PMID:Is GABA release modulated by presynaptic excitatory amino acid receptors? 197 34

The distribution and axonal transport of cholinergic organelles has been studied in the rat motor system, using immunofluorescence methods and a cytofluorimetric technique for quantification of immunoreactive material. Crush-operated spinal roots and sympathectomized sciatic nerves were sectioned longitudinally and incubated with antisera against p38, SV2, CGRP, chromogranin A (Chr A), synapsin I (SYN I), and with RASVA (rabbit anti-synaptic vesicle antiserum). Motor endplates were also studied. It was observed that proximally accumulating organelles--i.e., organelles which were in transport distally in the axons--contained RASVA-like immunoreactivity (LI) p38, SV2, CGRP-LI, Chr A-LI, and SYN I-LI. Retrogradely transported organelles, however, contained only p38 and SV2 in addition to RASVA-LI, but virtually no CGRP-LI, ChrA-LI, or SYN I-LI. It is suggested that the rapid axonal transport mechanism operates in the nerves like a chromatographic process, which allows the concentration in the axons, proximal or distal to the crush, of organelles in anterograde or retrograde transport, respectively. The technique of nerve crushes in combination with immunocytochemistry can therefore be used to investigate the biochemical composition of organelles in transit along the axon, and give information on neurobiological events occurring in these long processes leading to the nerve endings. In this study, biochemical differences between anterogradely and retrogradely transported cholinergic organelles in the motor neuron of the rat have been observed, and were related to suggested events in the endplate.
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PMID:Rapid axonal transport as a chromatographic process: the use of immunocytochemistry of ligated nerves to investigate the biochemistry of anterogradely versus retrogradely transported organelles. 246 Feb 58

The axonal transport of organelles in motor axons in the sympathectomized rat sciatic has been studied using two antisera which recognize specific components of synaptic vesicles. Anti-synapsin I recognizes synapsin I (SYN I) which is affiliated with the external membrane of synaptic vesicles, while rabbit-anti-synaptic vesicle antiserum (RASVA) recognizes integral membrane glycoproteins in cholinergic synaptic vesicles. Immunofluorescence studies, including cytofluorimetric scanning, show that immunoreactive (IR) material recognized by both antisera: rapidly accumulate proximal to a crush; the material has a granular appearance in the microscope; is redistributed in an isolated segment, and that the transport of the material is sensitive to vinblastine. Thus the proximodistal transport has the characteristics of fast axonal transport. Furthermore, recycling organelles, accumulating on the distal side of a crush are recognized by RASVA, but carry only very little SYN I-IR. The results give further support to the hypothesis that motor cholinergic axons transport axonal cholinergic vesicles towards the motor endplates.
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PMID:Axonal transport of synapsin I- and cholinergic synaptic vesicle-like material; further immunohistochemical evidence for transport of axonal cholinergic transmitter vesicles in motor neurons. 309 75

Thymic epithelial and nurse cells (TEC/TNC) synthesize an oxytocin (OT)-like peptide in association with a neurophysin (NP)-related protein in a way similar to in the hypothalamo-neurohypophysial (NHP) system. The central T-cell tolerance of the NHP neuroendocrine functions have been proposed to be mediated through these thymic NHP-related peptides due to their close homology with the NHP neurohormones OT and vasopressin (VP). In order to investigate their putative presentation by proteins of the major histocompatibility complex (MHC), human thymic membranes were purified and passed through an immunoaffinity column using mAb B9.12 directed to the monomorphic determinant of human MHC class I proteins. This methodology provided the following observations: (1) a NP-like protein is translocated in human thymic membranes and is retained by B9.12 on the column; (2) the MW of this NP-like material (50-55 kD) is quite different from the MW of hypothalamic NP proteins (10 kD), and (3) this thymic NP-like protein could be identified on Western blots with mAb B9.12. The precise extent of this relationship between the thymic NP-like protein and the Ig/MHC superfamily is actually investigated through the characterization of the genetic mechanisms responsible for the thymic expression of NHP-related peptides. Given the physiological importance of OT and of its binding to NP for transport along the axonal processes of the NHP tract, we postulate that, somewhat analogously, the thymic NP-/MHC class I-related protein could be involved in the presentation of the OT-like peptide to immature T-cells.
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PMID:Membrane translocation and relationship with MHC class I of a human thymic neurophysin-like protein. 830 78

The neural cell adhesion molecule NCAM plays an important role in axonal growth, learning, and memory. A signaling pathway has been elucidated in which clustering of the NCAM140 isoform in the neural plasma membrane stimulated the activating phosphorylation of mitogen-activated protein kinases (MAPKs) and the transcription factor cyclic AMP response-element binding protein (CREB). NCAM clustering transiently induced dual phosphorylation (activation) of the MAPKs ERK1 and ERK2 (extracellular signal-regulated kinases) by a pathway regulated by the focal adhesion kinase p125fak, p59fyn, Ras, and MAPK kinase. CREB phosphorylation at serine 133 induced by NCAM was dependent in part on an intact MAPK pathway. c-Jun N-terminal kinase, which is associated with apoptosis and cellular stress, was not activated by NCAM. Inhibition of the MAPK pathway in rat cerebellar neuron cultures selectively reduced NCAM-stimulated neurite outgrowth. These results define an NCAM signal transduction mechanism with the potential for modulating the expression of genes needed for axonal growth, survival, and synaptic plasticity.
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PMID:NCAM stimulates the Ras-MAPK pathway and CREB phosphorylation in neuronal cells. 1008 88

Nerve injury leads to the release of a number of cytokines which have been shown to play an important role in cellular activation after peripheral nerve injury. The members of the signal transducer and activator of transcription (STAT) gene family are the main mediators in the signal transduction pathway of cytokines. After phosphorylation, STAT proteins are transported into the nucleus and exhibit transcriptional activity. Following axotomy in rat regenerating facial and hypoglossal neurons, a transient increase of mRNA for JAK2, JAK3, STAT1, STAT3 and STAT5 was detected using in situ hybridization and semi-quantitative polymerase chain reaction (PCR). Of the investigated STAT molecules, only STAT3 protein was significantly increased. In addition, activation of STAT3 by phosphorylation on position Tyr705 and enhanced nuclear translocation was found within 3 h in neurons and after 1 day in astrocytes. Unexpectedly, STAT3 tyrosine phosphorylation was obvious for more than 3 months. In contrast, none of these changes was found in response to axotomy of non-regenerating Clarke's nucleus neurons, although all the investigated models express c-Jun and growth-associated protein-43 (GAP-43) in response to axonal injury. Increased expression of Janus kinase (JAK) and STAT molecules after peripheral nerve transection suggests changes in the responsiveness of the neurons to signalling molecules. STAT3 as a transcription factor, which is expressed early and is activated persistently until the time of reinnervation, might be involved in the switch from the physiological gene expression to an 'alternative program' activated only after peripheral nerve injury.
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PMID:Peripheral but not central axotomy induces changes in Janus kinases (JAK) and signal transducers and activators of transcription (STAT). 1076 48

Neuregulins signal cells by binding to an activating hetero- and homodimeric forms of the neuregulin receptors HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). Axonally derived neuregulin signals myelin forming cells of the central and peripheral nervous systems through different receptor complexes: oligodendrocytes through erbB2/erbB4 heterodimers and Schwann cells through erbB2/erbB3 heterodimers. Since the leading edge of myelinating cells interacts directly with the axonal surface, we were interested in determining if signaling molecules localized at the leading edge associate with activated neuregulin receptors. We found a novel association between neuregulin receptors and focal adhesion kinase (FAK) in primary cultures of Schwann cells. Following stimulation with ligand, maximal binding of FAK to HER2 occurred by 1 min whereas maximal binding to HER3 was delayed to approximately 7 min. FAK is localized in focal adhesions of Schwann cells. We have previously shown HER2 and HER3 are distributed evenly throughout the plasmalemma. Neuregulins thus use FAK to transmit intracellular signals and the differential kinetics of FAK association with individual neuregulin receptors, as well as its restricted subcellular localization, may play a role in specifying biologic responses.
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PMID:Neuregulin induces the rapid association of focal adhesion kinase with the erbB2-erbB3 receptor complex in schwann cells. 1079 11

Using an indirect immunohistochemical method, synaptophysin immunoreactivity (SYN-IR) has been studied in cryostat sections of stellate and thoracic ganglia in human fetuses, neonates, infants and adults. In the course of development, a progressive increase in SYN-IR in axonal terminals and around nerve cells was demonstrated. In contrast, large clusters of small intensely fluorescent (SIF) cells and paraganglionic cells increased in number in fetuses and premature neonates at 24-25 weeks. Such SIF cell clusters varied in form and often occurred at pole or subcapsular areas of sympathetic ganglia close to blood vessels or paraganglia. With increasing gestational age and during infancy, a decrease in sizes of SIF cell groups and paraganglionic cells as well as changes in their distribution were found. The results show that the amount and distribution of SYN-IR is temporally related to the maturation and functional activity of human sympathetic ganglia neurons. It was suggested that numerous SIF cells and paraganglia in human prenatal sympathetic ganglia were both indicative of incomplete cell migration and an important source of regulation of ganglionic microcirculation under the conditions of relative hypoxia and immature nervous regulation.
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PMID:The development of synaptophysin immunoreactivity in the human sympathetic ganglia. 1150 60

Specific neuronal populations in the basolateral amygdala (ABL) exhibit immunoreactivity for distinct neuropeptides and calcium-binding proteins. In the present study, immunohistochemical techniques were used to analyze neurons in the rat ABL that contain cholecystokinin (CCK). Some pyramidal projection neurons in the anterior subdivision of the basolateral nucleus exhibited low levels of CCK immunoreactivity in rats that received injections of colchicine to interrupt axonal transport; staining was concentrated in the axon initial segments of these cells. High levels of CCK immunoreactivity were observed in two subpopulations of nonpyramidal interneurons in all nuclei of the ABL: (1) type L neurons (characterized by large somata and thick dendrites), and (2) type S neurons (characterized by small somata and thin dendrites). Dual-labeling immunofluorescence studies using confocal laser scanning microscopy revealed that many (30-40%) type L CCK+ interneurons exhibited immunoreactivity for calbindin (CB), but not for parvalbumin (PV), calretinin (CR), or vasoactive intestinal polypeptide (VIP). In contrast, there was extensive colocalization of CR and VIP with CCK in type S neurons, but no significant colocalization with CB or PV. In addition, the majority of CR and VIP interneurons exhibited colocalization of both neurochemicals. Collectively, the results of this and previous studies indicate that there are at least four distinct interneuronal subpopulations in the ABL: (1) PV+ neurons (the great majority of which are CB+); (2) SOM+ neurons (many of which are CB+ and NPY+); (3) large CCK+ neurons (some of which are CB+); and (4) small bipolar/bitufted neurons that exhibit various amounts of colocalization of CCK, VIP, and CR.
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PMID:Immunohistochemical characterization of cholecystokinin containing neurons in the rat basolateral amygdala. 1276 51


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