Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.4.4 (kinesin)
5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At GABAergic synapses, GABA receptors form high-density clusters opposite GABA release sites. Whether GABA release per se plays a role in the formation of GABA receptor clusters remains uncertain. To address this question in vivo, we characterized GABA receptor clustering in the nematode Caenorhabditis elegans. In C. elegans, body wall muscles receive excitatory inputs from cholinergic motor neurons and inhibitory inputs from GABAergic neurons. Using immunohistochemistry and green fluorescent protein-tagged proteins, we observed that the muscle GABA receptor UNC-49 is precisely clustered opposite GABA release sites. During development, these clusters appear slightly after the detection of presynaptic vesicles. If motor axons are mislocalized as in unc-5 mutants, GABA receptors cluster opposite ectopic axons at GABA release sites. Together, these data imply that a motor neuron-derived factor is instructing GABA receptor clustering. Presynaptic localization of this clustering activity requires the neuronal kinesin UNC-104, suggesting that release of GABA from synaptic vesicles may represent the clustering signal. However, unc-25 mutants do not synthesize GABA but do cluster postsynaptic GABA receptors indistinguishably from the wild type. Therefore, at GABAergic neuromuscular junctions, GABA receptor clustering requires nerve-muscle interaction but not GABA neurotransmission.
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PMID:GABA is dispensable for the formation of junctional GABA receptor clusters in Caenorhabditis elegans. 1268 44

Gamma-aminobutyric acid(A) receptor-interacting factor (GRIF-1) is a 913-amino acid protein proposed to function as a GABA(A) receptor beta(2) subunit-interacting, trafficking protein. GRIF-1 shares approximately 44% amino acid sequence identity with O-linked N-acetylglucosamine transferase interacting protein 106, OIP106. Both proteins contain predicted coiled-coil domains and probably constitute a novel gene family. The Drosophila orthologue of this family of proteins may be Milton. Milton shares approximately 44% amino acid homology with GRIF-1. Milton is proposed to function in kinesin-mediated transport of mitochondria to nerve terminals. We report here that GRIF-1 and OIP106 also associate with kinesin and mitochondria. Following expression in human embryonic kidney 293 cells, both GRIF-1 and OIP106 were shown by co-immunoprecipitation to be specifically associated with an endogenous kinesin heavy chain species of 115 kDa and exogenous KIF5C. Association of GRIF-1 with kinesin was also evident in native brain and heart tissue. In the brain, anti-GRIF-1-(8-633) antibodies specifically co-immunoprecipitated two kinesin-immunoreactive species with molecular masses of 118 and 115 kDa, and in the heart, one kinesin-immunoreactive species, 115 kDa, was immunoprecipitated. Further studies revealed that GRIF-1 was predominantly associated with KIF5A in the brain and with KIF5B in both the heart and in HEK 293 cells. Yeast two-hybrid interaction assays and immunoprecipitations showed that GRIF-1 associated directly with KIF5C with the GRIF-1/KIF5C interaction domain localized to GRIF-1-(124-283). These results further support a role for GRIF-1 and OIP106 in protein and/or organelle transport in excitable cells in a manner analogous to glutamate receptor-interacting-protein 1, in the motor-dependent transport of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate excitatory neurotransmitter receptors to dendrites.
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PMID:GRIF-1 and OIP106, members of a novel gene family of coiled-coil domain proteins: association in vivo and in vitro with kinesin. 1564 24

To test the idea that caffeine might induce changes in gene expression in the honeybee brain, we contrasted the transcriptional profiles of control and caffeine-treated brains using high-throughput cDNA microarrays. Additional quantitative real-time PCR was performed on a subset of eight transcripts to visualize the temporal changes induced by caffeine. Genes that were significantly upregulated in caffeine-treated brains included those involved in synaptic signaling (GABA:Na symporter, dopamine D2R-like receptor, and synapsin), cytoskeletal modifications (kinesin and microtubule motors), protein translation (ribosomal protein RpL4, elongation factors), and calcium-dependent processes (calcium transporter, calmodulin- dependent cyclic nucleotide phosphodiesterase). In addition, our study uncovered a number of novel, caffeine-inducible genes that appear to be unique to the honeybee. Time-dependent profiling of caffeine-sensitive gene expression shows significant upregulation 1 h after treatment followed by moderate downregulation after 4 h with no additional changes occuring after 24 h. Our results provide initial evidence that the dopaminergic system and calcium exchange are the main targets of caffeine in the honeybee brain and suggest that molecular responses to caffeine in an invertebrate brain are similar to those in vertebrate organisms.
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PMID:Microarray and real-time PCR analyses of gene expression in the honeybee brain following caffeine treatment. 1628 May 96

GRIF-1 [GABA(A) (gamma-aminobutyric acid(A)) receptor interacting factor-1] is a member of a coiled-coil family of proteins thought to function as adaptors in the anterograde trafficking of organelles utilizing the kinesin-1 motor proteins to synapses. To study in more detail the molecular interaction between GRIF-1 and the kinesin-1 family member KIF5C, fluorescent yellow- and fluorescent cyan-tagged GRIF-1, KIF5C, the KIF5C MD (motor domain) and the KIF5C NMD (non-motor domain) fusion proteins were generated. Each was characterized with respect to size and ability to co-associate by immunoprecipitation following expression in HEK-293 (human embryonic kidney 293) cells. Further, their distribution in transfected HEK-293 and transformed African green monkey kidney (COS-7) cells was analysed by confocal microscopy. The fluorescent GRIF-1 and KIF5C fusion proteins were all found to behave as wild-type. Double GRIF-1/KIF5C transfectants revealed co-localization. The GRIF-1/KIF5C and GRIF-1/KIF5C NMD double transfectants showed different subcellular distributions compared with single GRIF-1, KIF5C or KIF5C NMD transfections. These studies confirm the association between GRIF-1 and kinesin-1 NMDs. Fluorescence resonance energy transfer studies are ongoing to characterize this interaction in more detail.
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PMID:GRIF-1-kinesin-1 interactions: a confocal microscopy study. 1641 80

Gamma-aminobutyric acid, type A (GABAA) receptor interacting factor-1 (GRIF-1) and N-acetylglucosamine transferase interacting protein (OIP) 106 are both members of a newly identified coiled-coil family of proteins. They are kinesin-associated proteins proposed to function as adaptors in the anterograde trafficking of organelles to synapses. Here we have studied in more detail the interaction between the prototypic kinesin heavy chain, KIF5C, kinesin light chain, and GRIF-1. The GRIF-1 binding site of KIF5C was mapped using truncation constructs in yeast two-hybrid interaction assays, co-immunoprecipitations, and co-localization studies following expression in mammalian cells. Using these approaches, it was shown that GRIF-1 and the KIF5C binding domain of GRIF-1, GRIF-1-(124-283), associated with the KIF5C non-motor domain. Refined studies using yeast two-hybrid interactions and co-immunoprecipitations showed that GRIF-1 and GRIF-1-(124-283) associated with the cargo binding region within the KIF5C non-motor domain. Substantiation that the GRIF-1-KIF5C interaction was direct was shown by fluorescence resonance energy transfer analyses using fluorescently tagged GRIF-1 and KIF5C constructs. A significant fluorescence resonance energy transfer value was found between the C-terminal EYFP-tagged KIF5C and ECFP-GRIF-1, the C-terminal EYFP-tagged KIF5C non-motor domain and ECFP-GRIF-1, but not between the N-terminal EYFP-tagged KIF5C nor the EYFP-KIF5C motor domain and ECFP-GRIF-1, thus confirming direct association between the two proteins at the KIF5C C-terminal and GRIF-1 N-terminal regions. Co-immunoprecipitation and confocal imaging strategies further showed that GRIF-1 can bind to the tetrameric kinesin light-chain/kinesin heavy-chain complex. These findings support a role for GRIF-1 as a kinesin adaptor molecule requisite for the anterograde delivery of defined cargoes such as mitochondria and/or vesicles incorporating beta2 subunit-containing GABAA receptors, in the brain.
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PMID:Mapping the GRIF-1 binding domain of the kinesin, KIF5C, substantiates a role for GRIF-1 as an adaptor protein in the anterograde trafficking of cargoes. 1683 41

The cytoskeleton and cytoskeletal motors play a fundamental role in neurotransmitter receptor trafficking, but proteins that link GABA(B) receptors (GABA(B)Rs) to the cytoskeleton have not been described. We recently identified Marlin-1, a protein that interacts with GABA(B)R1. Here, we explore the association of GABA(B)Rs and Marlin-1 to the cytoskeleton using a combination of biochemistry, microscopy and live cell imaging. Our results indicate that Marlin-1 is associated to microtubules and the molecular motor kinesin-I. We demonstrate that a fraction of Marlin-1 is mobile in dendrites of cultured hippocampal neurons and that mobility is microtubule-dependent. We also show that GABA(B)Rs interact robustly with kinesin-I and that intracellular membranes containing GABA(B)Rs are sensitive to treatments that disrupt a protein complex containing Marlin-1, kinesin-I and tubulin. Finally, we report that a kinesin-I mutant severely impairs receptor transport. We conclude that Marlin-1 and kinesin-1 link GABA(B)Rs to the tubulin cytoskeleton in neurons.
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PMID:Marlin-1 and conventional kinesin link GABAB receptors to the cytoskeleton and regulate receptor transport. 1753 44

The density of GABA(A) receptors (GABA(A)Rs) at synapses regulates brain excitability, and altered inhibition may contribute to Huntington's disease, which is caused by a polyglutamine repeat in the protein huntingtin. However, the machinery that delivers GABA(A)Rs to synapses is unknown. We demonstrate that GABA(A)Rs are trafficked to synapses by the kinesin family motor protein 5 (KIF5). We identify the adaptor linking the receptors to KIF5 as the huntingtin-associated protein 1 (HAP1). Disrupting the HAP1-KIF5 complex decreases synaptic GABA(A)R number and reduces the amplitude of inhibitory postsynaptic currents. When huntingtin is mutated, as in Huntington's disease, GABA(A)R transport and inhibitory synaptic currents are reduced. Thus, HAP1-KIF5-dependent GABA(A)R trafficking is a fundamental mechanism controlling the strength of synaptic inhibition in the brain. Its disruption by mutant huntingtin may explain some of the defects in brain information processing occurring in Huntington's disease and provides a molecular target for therapeutic approaches.
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PMID:Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. 2015 13

In the retina, dopamine fulfills a crucial role in neural adaptation to photopic illumination, but the pathway that carries cone signals to the dopaminergic amacrine (DA) cells was controversial. We identified the site of ON-cone bipolar input onto DA cells in transgenic mice in which both types of catecholaminergic amacrine (CA) cells were labeled with green fluorescent protein or human placental alkaline phosphatase (PLAP). In confocal Z series of retinal whole mounts stained with antibodies to tyrosine hydroxylase (TH), DA cells gave rise to varicose processes that descended obliquely through the scleral half of the inner plexiform layer (IPL) and formed a loose, tangential plexus in the middle of this layer. Comparison with the distribution of the dendrites of type 2 CA cells and examination of neurobiotin-injected DA cells proved that their vitreal processes were situated in stratum S3 of the IPL. Electron microscope demonstration of PLAP activity showed that bipolar cell endings in S3 established ribbon synapses onto a postsynaptic dyad in which one or both processes were labeled by a precipitate of lead phosphate and therefore belonged to DA cells. In places, the postsynaptic DA cell processes returned a reciprocal synapse onto the bipolar endings. Confocal images of sections stained with antibodies to TH, kinesin Kif3a, which labels synaptic ribbons, and glutamate or GABA(A) receptors, confirmed that ribbon-containing endings made glutamatergic synapses onto DA cells processes in S3 and received from them GABAergic synapses. The presynaptic ON-bipolar cells most likely belonged to the CB3 (type 5) variety.
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PMID:Synaptic input of ON-bipolar cells onto the dopaminergic neurons of the mouse retina. 2039 57

Growing evidence suggests that Huntington's disease (HD), a neurodegenerative movement disorder caused by the mutant huntingtin (htt) with an expanded polyglutamine (polyQ) repeat, is associated with the altered intracellular trafficking and synaptic function. GABA(A) receptors, the key determinant of the strength of synaptic inhibition, have been found to bind to the huntingtin associated protein 1 (HAP1). HAP1 serves as an adaptor linking GABA(A) receptors to the kinesin family motor protein 5 (KIF5), controlling the transport of GABA(A) receptors along microtubules in dendrites. In this study, we found that GABA(A)R-mediated synaptic transmission is significantly impaired in a transgenic mouse model of HD expressing polyQ-htt, which is accompanied by the diminished surface expression of GABA(A) receptors. Moreover, the GABA(A)R/HAP1/KIF5 complex is disrupted and dissociated from microtubules in the HD mouse model. These results suggest that GABA(A)R trafficking and function is impaired in HD, presumably due to the interference of KIF5-mediated microtubule-based transport of GABA(A) receptors. The diminished inhibitory synaptic efficacy could contribute to the loss of the excitatory/inhibitory balance, leading to increased neuronal excitotoxicity in HD.
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PMID:Disrupted GABAAR trafficking and synaptic inhibition in a mouse model of Huntington's disease. 2240 31

Proper localization of various ion channels is fundamental to neuronal functions, including postsynaptic potential plasticity, dendritic integration, action potential initiation and propagation, and neurotransmitter release. Microtubule-based forward transport mediated by kinesin motors plays a key role in placing ion channel proteins to correct subcellular compartments. PDZ- and coiled-coil-domain proteins function as adaptor proteins linking ionotropic glutamate and GABA receptors to various kinesin motors, respectively. Recent studies show that several voltage-gated ion channel/transporter proteins directly bind to kinesins during forward transport. Three major regulatory mechanisms underlying intracellular transport of ion channels are also revealed. These studies contribute to understanding how mechanical forces are coupled to electrical signaling and illuminating pathogenic mechanisms in neurodegenerative diseases.
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PMID:Coupling mechanical forces to electrical signaling: molecular motors and the intracellular transport of ion channels. 2291 31


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