Selective inhibition of retrograde axonal transport byerythro-9-[3-(-2-hydroxynonyl)]adenine

Forman, David S.; Brown, Kurt J.; Promersberger, Mark E.

doi:10.1016/0006-8993(83)90381-5

Cited by 46 publications

(12 citation statements)

References 16 publications

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“…Goldberg, 1982;Ekstrom and Kanje, 1984;Forman et al, 1983;Schnapp and Reese, 1989;Wang et al, 1995). The only alternative appears to be the minus-end-directed kinesin-14 motors.…”

Section: Dynein Motorsmentioning

confidence: 99%

The axonal transport of mitochondria

Hollenbeck

Saxton

2005

Journal of Cell Science

732

680

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Organelle transport is vital for the development and maintenance of axons, in which the distances between sites of organelle biogenesis, function, and recycling or degradation can be vast. Movement of mitochondria in axons can serve as a general model for how all organelles move: mitochondria are easy to identify, they move along both microtubule and actin tracks, they pause and change direction, and their transport is modulated in response to physiological signals. However, they can be distinguished from other axonal organelles by the complexity of their movement and their unique functions in aerobic metabolism, calcium homeostasis and cell death. Mitochondria are thus of special interest in relating defects in axonal transport to neuropathies and degenerative diseases of the nervous system. Studies of mitochondrial transport in axons are beginning to illuminate fundamental aspects of the distribution mechanism. They use motors of one or more kinesin families, along with cytoplasmic dynein, to translocate along microtubules, and bidirectional movement may be coordinated through interaction between dynein and kinesin-1. Translocation along actin filaments is probably driven by myosin V, but the protein(s) that mediate docking with actin filaments remain unknown. Signaling through the PI 3-kinase pathway has been implicated in regulation of mitochondrial movement and docking in the axon, and additional mitochondrial linker and regulatory proteins, such as Milton and Miro, have recently been described.

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“…Goldberg, 1982;Ekstrom and Kanje, 1984;Forman et al, 1983;Schnapp and Reese, 1989;Wang et al, 1995). The only alternative appears to be the minus-end-directed kinesin-14 motors.…”

Section: Dynein Motorsmentioning

confidence: 99%

The axonal transport of mitochondria

Hollenbeck

Saxton

2005

Journal of Cell Science

732

680

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“…This relatively high degree of specificity led to the suggestion that EHNA could be used as a probe for the putative participation of cytoplasmic dyneins in several forms of cytoplasmic motility. Indeed, subsequent studies showed that EHNA blocks certain forms of microtubulebased motility (4)(5)(6)(7)(8). These observations were taken as indirect evidence for the involvement of a cytoplasmic dyneinlike ATPase.…”

mentioning

confidence: 99%

“…Its potential usefulness in the search for "cytoplasmic" dyneins involved in motility phenomena, such as intracellular transport, was immediately realized. Thus, in addition to its use in the study of the properties of ciliary and flagellar dynein (2, 3), EHNA has been employed as a probe for the possible involvement of dynein-like ATPases in chromosome movement in mitosis (4), particle transport in chromatophores (5, 6), and organelle movements along axons (7,8). Inhibition of these forms of motility by EHNA has been taken as an indication for the involvement of a cytoplasmic, possibly microtubule-associated, dynein ATPase activity.…”

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confidence: 99%

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erythro-9-[3-(2-Hydroxynonyl)]adenine is an effective inhibitor of cell motility and actin assembly.

Schliwa¹,

Ezzell²,

Euteneuer³

1984

Proc. Natl. Acad. Sci. U.S.A.

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erythro-9-[3-(2-Hydroxynonyl)Jadenine (EHNA) has been reported previously to be an agent that arrests sperm motility by inhibiting the axonemal dynein ATPase activity and has been used to probe the involvement of putative cytoplasmic dyneins in mitosis and intracellular organelle transport. We report here that EHNA profoundly and reversibly affects several actin-dependent processes, both in vivo and in vitro. It induces dramatic changes in actin organization in cultured cells, inhibits cell translocation, blocks actin-dependent cytoplasmic streaming, interferes with actin-dependent gelation of cytoplasmic extracts, and inhibits actin assembly. Just as the cytochalasins, -EHNA appears to be a highly effective inhibitor of actin-based motility, whose effects in complex biological systems should be interpreted with caution.Analysis of the function of cytoskeletal components greatly profits from the use of specific inhibitors. Prime examples include colchicine, which depolymerizes microtubules and inhibits their assembly, and the cytochalasins, which decrease the rate of actin assembly and interfere with actin network formation. Such inhibitors, of which colchicine and cytochalasin are just two of the most widely known, have become invaluable tools in research on cell motility. Recently, an inhibitor of dynein ATPase activity, erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA), became available, which, unlike vanadate, another potent dynein inhibitor (1), can easily cross the cell membrane and thus can be applied to living cells (2). Its potential usefulness in the search for "cytoplasmic" dyneins involved in motility phenomena, such as intracellular transport, was immediately realized. Thus, in addition to its use in the study of the properties of ciliary and flagellar dynein (2, 3), EHNA has been employed as a probe for the possible involvement of dynein-like ATPases in chromosome movement in mitosis (4), particle transport in chromatophores (5, 6), and organelle movements along axons (7,8). Inhibition of these forms of motility by EHNA has been taken as an indication for the involvement of a cytoplasmic, possibly microtubule-associated, dynein ATPase activity.In the course of studies on intracellular organelle movements using EHNA, we noted effects of this compound apparently unrelated to a possible action on dynein-like molecules. Here we report that EHNA interferes with the functional organization of actin in vivo and in vitro. It profoundly affects actin filament organization in cultured cells, reversibly interferes with actin-dependent forms of motility, and inhibits gel formation of cytoplasmic extracts and actin assembly in vitro. Next to the cytochalasins, it is probably one of the most effective inhibitors of actin-based motility.MATERIALS AND METHODS Cells. African green monkey kidney cells (strain BSC-1) were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (GIBCO). For experiments, cells were seeded on coverslips and were used in the exponential growth phase. M...

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“…If kinesin functions in axonal transport it might work in addition to, or conceivably in conjunction with, a different mechanochemical system. In particular, there is reason to believe that the motile machinery for transport in the two directions in the axon-toward and away from the cell bodymay be different (2,13). This notion has been reinforced by the finding that kinesin generates force in just one direction along microtubules-from the minus toward the plus ends (38).…”

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confidence: 99%

A novel microtubule-associated protein from mammalian nerve shows ATP-sensitive binding to microtubules.

Hollenbeck¹,

Chapman²

1986

The Journal of Cell Biology

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Abstract. We report the isolation of a protein from mammalian nerve which shows ATP-sensitive binding to microtubules and ATPase activity. This protein, which we have designated HMW4, was prepared from bovine spinal nerve roots by microtubule affinity and ATP-induced release, and was further purified by sucrose density gradient centrifugation. It is a high molecular weight protein with a denatured Mr of 315,000, a Stokes radius of 90/~, and a sedimentation value of ,,o19S. It can be resolved electrophoretically from the well-characterized bovine brain microtubuleassociated proteins (MAPs) and also appears to be distinct from MAP 1C. HMW4 has a vanadate-sensitive and azide-insensitive ATPase activity which averages 20 nmol Pi/min per mg protein and is different from dynein and myosin ATPases. HMW4 prepared on sucrose gradients exhibits binding to MAP-free microtubules in the absence of ATP which is reduced by ATP addition. Assayed by darkfield microscopy, HMW4 causes bundling of MAP-free microtubules which is reversed by ATP addition.

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Selective inhibition of retrograde axonal transport byerythro-9-[3-(-2-hydroxynonyl)]adenine

Cited by 46 publications

References 16 publications

The axonal transport of mitochondria

The axonal transport of mitochondria

erythro-9-[3-(2-Hydroxynonyl)]adenine is an effective inhibitor of cell motility and actin assembly.

A novel microtubule-associated protein from mammalian nerve shows ATP-sensitive binding to microtubules.

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