Abstract
To investigate the possibility that kinesin transports vesicles bearing proteins essential for ion channel activity, the effects of kinesin (Khc) and ion channel mutations were compared in Drosophila using established tests. Our results show that Khc mutations produce defects and genetic interactions characteristic of paralytic (para) and maleless (mle) mutations that cause reduced expression or function of the alpha-subunit of voltage-gated sodium channels. Like para and mle mutations, Khc mutations cause temperature-sensitive (TS) paralysis. When combined with para or mle mutations, Khc mutations cause synthetic lethality and a synergistic enhancement of TS-paralysis. Furthermore, Khc mutations suppress Shaker and ether-a-go-go mutations that disrupt potassium channel activity. In light of previous physiological tests that show that Khc mutations inhibit compound action potential propagation in segmental nerves, these data indicate that kinesin activity is required for normal inward sodium currents during neuronal action potentials. Tests for phenotypic similarities and genetic interactions between kinesin and sodium/potassium ATPase mutations suggest that impaired kinesin function does not affect the driving force on sodium ions. We hypothesize that a loss of kinesin function inhibits the anterograde axonal transport of vesicles bearing sodium channels.
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- Aizawa H., Sekine Y., Takemura R., Zhang Z., Nangaku M., Hirokawa N. Kinesin family in murine central nervous system. J Cell Biol. 1992 Dec;119(5):1287–1296. doi: 10.1083/jcb.119.5.1287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Atwood H. L., Govind C. K., Wu C. F. Differential ultrastructure of synaptic terminals on ventral longitudinal abdominal muscles in Drosophila larvae. J Neurobiol. 1993 Aug;24(8):1008–1024. doi: 10.1002/neu.480240803. [DOI] [PubMed] [Google Scholar]
- Berliner E., Young E. C., Anderson K., Mahtani H. K., Gelles J. Failure of a single-headed kinesin to track parallel to microtubule protofilaments. Nature. 1995 Feb 23;373(6516):718–721. doi: 10.1038/373718a0. [DOI] [PubMed] [Google Scholar]
- Bloom G. S., Endow S. A. Motor proteins. 1: kinesins. Protein Profile. 1994;1(10):1059–1116. [PubMed] [Google Scholar]
- Brady S. T. Molecular motors in the nervous system. Neuron. 1991 Oct;7(4):521–533. doi: 10.1016/0896-6273(91)90365-7. [DOI] [PubMed] [Google Scholar]
- Catterall W. A. Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev. 1992 Oct;72(4 Suppl):S15–S48. doi: 10.1152/physrev.1992.72.suppl_4.S15. [DOI] [PubMed] [Google Scholar]
- De Biasi S., Rustioni A. Glutamate and substance P coexist in primary afferent terminals in the superficial laminae of spinal cord. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7820–7824. doi: 10.1073/pnas.85.20.7820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Elkins T., Ganetzky B. Conduction in the giant nerve fiber pathway in temperature-sensitive paralytic mutants of Drosophila. J Neurogenet. 1990 Aug;6(4):207–219. doi: 10.3109/01677069009107111. [DOI] [PubMed] [Google Scholar]
- Feng G., Deák P., Kasbekar D. P., Gil D. W., Hall L. M. Cytogenetic and molecular localization of tipE: a gene affecting sodium channels in Drosophila melanogaster. Genetics. 1995 Apr;139(4):1679–1688. doi: 10.1093/genetics/139.4.1679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ganetzky B. Neurogenetic analysis of Drosophila mutations affecting sodium channels: synergistic effects on viability and nerve conduction in double mutants involving tip-E. J Neurogenet. 1986 Jan;3(1):19–31. doi: 10.3109/01677068609106892. [DOI] [PubMed] [Google Scholar]
- Ganetzky B., Wu C. F. Drosophila mutants with opposing effects on nerve excitability: genetic and spatial interactions in repetitive firing. J Neurophysiol. 1982 Mar;47(3):501–514. doi: 10.1152/jn.1982.47.3.501. [DOI] [PubMed] [Google Scholar]
- Ganetzky B., Wu C. F. Indirect Suppression Involving Behavioral Mutants with Altered Nerve Excitability in DROSOPHILA MELANOGASTER. Genetics. 1982 Apr;100(4):597–614. doi: 10.1093/genetics/100.4.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goldstein L. S. With apologies to scheherazade: tails of 1001 kinesin motors. Annu Rev Genet. 1993;27:319–351. doi: 10.1146/annurev.ge.27.120193.001535. [DOI] [PubMed] [Google Scholar]
- Goodson H. V., Kang S. J., Endow S. A. Molecular phylogeny of the kinesin family of microtubule motor proteins. J Cell Sci. 1994 Jul;107(Pt 7):1875–1884. doi: 10.1242/jcs.107.7.1875. [DOI] [PubMed] [Google Scholar]
- Grafstein B., Forman D. S. Intracellular transport in neurons. Physiol Rev. 1980 Oct;60(4):1167–1283. doi: 10.1152/physrev.1980.60.4.1167. [DOI] [PubMed] [Google Scholar]
- HODGKIN A. L., KATZ B. The effect of temperature on the electrical activity of the giant axon of the squid. J Physiol. 1949 Aug;109(1-2):240–249. doi: 10.1113/jphysiol.1949.sp004388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hackney D. D. Evidence for alternating head catalysis by kinesin during microtubule-stimulated ATP hydrolysis. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6865–6869. doi: 10.1073/pnas.91.15.6865. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hall D. H., Hedgecock E. M. Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans. Cell. 1991 May 31;65(5):837–847. doi: 10.1016/0092-8674(91)90391-b. [DOI] [PubMed] [Google Scholar]
- Hirokawa N. Axonal transport and the cytoskeleton. Curr Opin Neurobiol. 1993 Oct;3(5):724–731. doi: 10.1016/0959-4388(93)90144-n. [DOI] [PubMed] [Google Scholar]
- Huffaker T. C., Hoyt M. A., Botstein D. Genetic analysis of the yeast cytoskeleton. Annu Rev Genet. 1987;21:259–284. doi: 10.1146/annurev.ge.21.120187.001355. [DOI] [PubMed] [Google Scholar]
- Jackson F. R., Wilson S. D., Hall L. M. The tip-E mutation of Drosophila decreases saxitoxin binding and interacts with other mutations affecting nerve membrane excitability. J Neurogenet. 1986 Jan;3(1):1–17. doi: 10.3109/01677068609106891. [DOI] [PubMed] [Google Scholar]
- Jackson F. R., Wilson S. D., Strichartz G. R., Hall L. M. Two types of mutants affecting voltage-sensitive sodium channels in Drosophila melanogaster. Nature. 1984 Mar 8;308(5955):189–191. doi: 10.1038/308189a0. [DOI] [PubMed] [Google Scholar]
- Kaiser C. A., Schekman R. Distinct sets of SEC genes govern transport vesicle formation and fusion early in the secretory pathway. Cell. 1990 May 18;61(4):723–733. doi: 10.1016/0092-8674(90)90483-u. [DOI] [PubMed] [Google Scholar]
- Kamb A., Iverson L. E., Tanouye M. A. Molecular characterization of Shaker, a Drosophila gene that encodes a potassium channel. Cell. 1987 Jul 31;50(3):405–413. doi: 10.1016/0092-8674(87)90494-6. [DOI] [PubMed] [Google Scholar]
- Kaplan W. D., Trout W. E., 3rd The behavior of four neurological mutants of Drosophila. Genetics. 1969 Feb;61(2):399–409. doi: 10.1093/genetics/61.2.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kernan M. J., Kuroda M. I., Kreber R., Baker B. S., Ganetzky B. napts, a mutation affecting sodium channel activity in Drosophila, is an allele of mle, a regulator of X chromosome transcription. Cell. 1991 Sep 6;66(5):949–959. doi: 10.1016/0092-8674(91)90440-a. [DOI] [PubMed] [Google Scholar]
- Loughney K., Kreber R., Ganetzky B. Molecular analysis of the para locus, a sodium channel gene in Drosophila. Cell. 1989 Sep 22;58(6):1143–1154. doi: 10.1016/0092-8674(89)90512-6. [DOI] [PubMed] [Google Scholar]
- Mercer J. A., Albanesi J. P., Brady S. T. Molecular motors and cell motility in the brain. Brain Pathol. 1994 Apr;4(2):167–179. doi: 10.1111/j.1750-3639.1994.tb00827.x. [DOI] [PubMed] [Google Scholar]
- Nelson J. C., Wyman R. J. Examination of paralysis in Drosophila temperature-sensitive paralytic mutations affecting sodium channels; a proposed mechanism of paralysis. J Neurobiol. 1990 Apr;21(3):453–469. doi: 10.1002/neu.480210307. [DOI] [PubMed] [Google Scholar]
- Okada Y., Yamazaki H., Sekine-Aizawa Y., Hirokawa N. The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell. 1995 Jun 2;81(5):769–780. doi: 10.1016/0092-8674(95)90538-3. [DOI] [PubMed] [Google Scholar]
- Papazian D. M., Schwarz T. L., Tempel B. L., Jan Y. N., Jan L. Y. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science. 1987 Aug 14;237(4816):749–753. doi: 10.1126/science.2441470. [DOI] [PubMed] [Google Scholar]
- Saxton W. M., Hicks J., Goldstein L. S., Raff E. C. Kinesin heavy chain is essential for viability and neuromuscular functions in Drosophila, but mutants show no defects in mitosis. Cell. 1991 Mar 22;64(6):1093–1102. doi: 10.1016/0092-8674(91)90264-y. [DOI] [PubMed] [Google Scholar]
- Schubiger M., Feng Y., Fambrough D. M., Palka J. A mutation of the Drosophila sodium pump alpha subunit gene results in bang-sensitive paralysis. Neuron. 1994 Feb;12(2):373–381. doi: 10.1016/0896-6273(94)90278-x. [DOI] [PubMed] [Google Scholar]
- Stern M., Ganetzky B. Identification and characterization of inebriated, a gene affecting neuronal excitability in Drosophila. J Neurogenet. 1992 Sep;8(3):157–172. doi: 10.3109/01677069209083445. [DOI] [PubMed] [Google Scholar]
- Stern M., Kreber R., Ganetzky B. Dosage effects of a Drosophila sodium channel gene on behavior and axonal excitability. Genetics. 1990 Jan;124(1):133–143. doi: 10.1093/genetics/124.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stewart R. J., Pesavento P. A., Woerpel D. N., Goldstein L. S. Identification and partial characterization of six members of the kinesin superfamily in Drosophila. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8470–8474. doi: 10.1073/pnas.88.19.8470. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Suzuki D. T., Grigliatti T., Williamson R. Temperature-sensitive mutations in Drosophila melanogaster. VII. A mutation (para-ts) causing reversible adult paralysis. Proc Natl Acad Sci U S A. 1971 May;68(5):890–893. doi: 10.1073/pnas.68.5.890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tanouye M. A., Ferrus A. Action potentials in normal and Shaker mutant Drosophila. J Neurogenet. 1985 Sep;2(4):253–271. doi: 10.3109/01677068509102322. [DOI] [PubMed] [Google Scholar]
- Trout W. E., Kaplan W. D. Genetic manipulation of motor output in shaker mutants of Drosophila. J Neurobiol. 1973;4(6):495–512. doi: 10.1002/neu.480040603. [DOI] [PubMed] [Google Scholar]
- Vallee R. B., Bloom G. S. Mechanisms of fast and slow axonal transport. Annu Rev Neurosci. 1991;14:59–92. doi: 10.1146/annurev.ne.14.030191.000423. [DOI] [PubMed] [Google Scholar]
- Warmke J., Drysdale R., Ganetzky B. A distinct potassium channel polypeptide encoded by the Drosophila eag locus. Science. 1991 Jun 14;252(5012):1560–1562. doi: 10.1126/science.1840699. [DOI] [PubMed] [Google Scholar]
- Wu C. F., Ganetzky B., Jan L. Y., Jan Y. N., Benzer S. A Drosophila mutant with a temperature-sensitive block in nerve conduction. Proc Natl Acad Sci U S A. 1978 Aug;75(8):4047–4051. doi: 10.1073/pnas.75.8.4047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu C. F., Ganetzky B. Neurogenetic studies of ion channels in Drosophila. Ion Channels. 1992;3:261–314. doi: 10.1007/978-1-4615-3328-3_9. [DOI] [PubMed] [Google Scholar]