Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examines the microtubule configuration and its close association with the Golgi complex and Golgi-derived membranous vesicles in elongating fiber cells of the rat lens. Since fiber cells elongate tremendously during lens differentiation, we hypothesize that a microtubule-based motor system exists in the elongating fiber cells for transporting important membrane proteins and organelles to the target regions for cell growth. The newly synthesized membrane proteins are known to be transported from the trans-Golgi network in the form of vesicles to the target plasma membrane. By thin-section TEM, we observed a large number of vesicles of various sizes and shapes randomly distributed throughout the cytoplasm of elongating fiber cells. Both Golgi complex and vesicles exhibited characteristic normal structural features seen in other cell types and thus represented real vesicular organelles in the fiber cells. A large number of microtubules were regularly arranged into bundles parallel to the long axis of fiber cells as examined in both longitudinal and cross-section views. Many of these microtubules were closely associated or in intimate contact with the Golgi complex and vesicles in elongating fiber cells. The microtubule polarity assay revealed that microtubules exhibited a unidirectional polarity for the entire length of fiber cells as examined in both anterior and posterior cortical fiber segments. Namely, the minus end of microtubules was towards the anterior lens pole while the plus end was headed towards the posterior pole. This suggests that multiple molecular motors such as kinesin and dynein are needed for carrying the vesicles to both lens poles, since conventional kinesin is known to transport vesicular organelles towards the plus end whereas cytoplasmic dynein carries them towards the minus end of microtubules. By immunoblot analysis, we indeed detected the presence of both kinesin (120 kD) and dynein (70 kD) in homogenate prepared from lens cortical fibers. Moreover, immunogold TEM demonstrated that the aquaporin 0 (formally MIP26) antibody was localized on the membranous vesicles as well as plasma membranes of the cortical fiber cells. This study suggests that a microtubule-based motor system exists in the lens and plays an important role in transporting membrane proteins such as aquaporin 0 in the vesicles during fiber cell differentiation and elongation.
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PMID:Microtubule configuration and membranous vesicle transport in elongating fiber cells of the rat lens. 1455 Apr 4

Lithium has been the gold standard in the treatment of bipolar disorder (BPD) for 60 y. Like lithium, glycogen synthase kinase 3 (GSK-3) inhibitors display both antimanic-like and antidepressant-like effects in some animal models. However, the molecular mechanisms of both lithium and GSK-3 inhibitors remain unclear. Here we show that the GSK-3 inhibitor AR-A014418 regulated alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-induced GluR1 and GluR2 internalization via phosphorylation of kinesin light chain 2 (KLC2), the key molecule of the kinesin cargo delivery system. Specifically, AMPA stimulation triggered serine phosphorylation of KLC2 and, subsequently, the dissociation of the GluR1/KLC2 protein complex. This suggests that GSK-3 phosphorylation of KLC2 led to the dissociation of AMPA-containing vesicles from the kinesin cargo system. The peptide TAT-KLCpCDK, a specific inhibitor for KLC2 phosphorylation by GSK-3beta, reduced the formation of long-term depression. Furthermore, the TAT-KLCpCDK peptide showed antimanic-like effects similar to lithium's on amphetamine-induced hyperactivity, a frequently used animal model of mania. It also induced antidepressant-like effects in the tail suspension and forced swim tests, two commonly used animal models of depression. Taken together, the results demonstrated that KLC2 is a cellular target of GSK-3beta capable of regulating synaptic plasticity, particularly AMPA receptor trafficking, as well as mood-associated behaviors in animal models. The kinesin cargo system may provide valuable novel targets for the development of new therapeutics for mood disorders.
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PMID:A kinesin signaling complex mediates the ability of GSK-3beta to affect mood-associated behaviors. 2053 17

The number of functional transient receptor potential vanilloid 1 (TRPV1) channels at the surface, especially at the peripheral terminals of primary sensory neurons, regulates heat sensitivity, and increased surface localization of TRPV1s contributes to heat hyperalgesia. However, the mechanisms for regulating TRPV1 surface localization are essentially unknown. Here, we show that cyclin-dependent kinase 5 (Cdk5), a new player in thermal pain sensation, positively regulates TRPV1 surface localization. Active Cdk5 was found to promote TRPV1 anterograde transport in vivo, suggesting a regulatory role of Cdk5 in TRPV1 membrane trafficking. TRPV1-containing vesicles bind to the forkhead-associated (FHA) domain of the KIF13B (kinesin-3 family member 13B) and are thus delivered to the cell surface. Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport. Moreover, complete Freund's adjuvant (CFA) injection-induced activation of Cdk5 increased the anterograde transport of TRPV1s, contributing to the development and possibly the maintenance of heat hyperalgesia, whereas intrathecal delivery of the TAT-T506 peptide alleviated CFA-induced heat hyperalgesia in rats. Thus, Cdk5 regulation of TRPV1 membrane trafficking is a fundamental mechanism controlling the heat sensitivity of nociceptors, and moderate inhibition of Thr-506 phosphorylation during inflammation might be helpful for the treatment of inflammatory thermal pain.
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PMID:Cyclin-dependent kinase 5 controls TRPV1 membrane trafficking and the heat sensitivity of nociceptors through KIF13B. 2307 56