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Lawrence B. Salkoff

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Lawrence B. Salkoff (born March 3, 1944) is an American neuroscientist and currently a professor of neuroscience and genetics at Washington University School of Medicine[1]

Lawrence B. Salkoff
Lawrence B. Salkoff

Early life and education

Salkoff received his Bachelor of Arts (B.A.) degree in economics in 1967 from University of California-Los Angeles. After graduation he volunteered in the United States Peace Corps working in Colombia, South America, from 1967 to 1970. Upon Salkoff's return to the United States he studied at the University of California, Berkeley, where he received his PhD in neurogenetics in 1979. Subsequently, Salkoff trained as a postdoctoral associate in neurogenetics at Yale University, in the laboratory of Professor Robert Wyman with consultation and aid from Professor Charles F. Stevens.

Career

Salkoff's career began in 1978 before much detail was known about ion channel structure using Drosophila as a model system. As a graduate student he worked on the shibire mutant and characterized its defects in synaptic transmission.[2]

Cloning of the extended family of potassium channel genes. The structure of potassium channels which shape the electrical activity in the nervous system was unknown when Salkoff was a graduate student. It was believed that one way to obtain the protein structure of a potassium channel was to identify a gene encoding the channel protein in a genetically tractable organism, and then combine newly developed tools in biophysics, molecular genetics, DNA sequencing in eukaryotes, and molecular cloning, to clone and sequence the gene and functionally express the encoded channel in a heterologous expression system. To this end, as a postdoctoral researcher, Salkoff adapted the voltage clamp technique to the fruit fly Drosophila which had been used by Alan Lloyd Hodgkin and Andrew Huxley to reveal the ionic basis of the nerve action potential.[3] This enabled the direct observation of ion currents in a genetically tractable organism.[4][5][6][7]

This technique was then used to show that the Drosophila Shaker gene was the structural gene for a potassium channel, a claim which was based on several genetic criteria and confirmed by biophysical analysis of the expected ion channel current phenotype. Thus, mutations of a structural gene should produce loss of function mutations where the gene product is absent or non-functional, gain of function mutations where the functional properties of the gene product is changed, and position effect mutations where a breakpoint near the gene reduces expression of a normal gene product. All three classes of mutations were characterized by Salkoff, e.g. 1. Loss-of-function mutant ( ShrKO120) which removed the Shaker K+ current.[6] 2. Gain-of-function mutant (Sh5) (which changed the inactivation kinetics of the current,[6] 3. Position effect conferred by the W32 X-chromosome breakpoint.[8]

Salkoff also combined voltage-clamp technique with genetic analysis to reveal the location of the Shaker gene on the Drosophila polytene chromosome map.[8] These studies validated the Shaker gene as the structural locus of a potassium channel and guided a chromosomal “walking” strategy to the physical location of the Shaker locus. It also had the effect of directing great attention to Drosophila as a model system combining molecular genetics with biophysical tools and enabled the study of ion channel biology using a comprehensive approach not possible in other systems.

Salkoff found that the W32 chromosomal broke within or close to the Shaker gene.[8] This study showing the location of the Shaker gene on the physical chromosome map facilitated the cloning of the Shaker potassium channel. Based on these findings Salkoff began a genomic DNA "walk" along the chromosome to clone the Shaker gene in conjunction with Patrick H. O'Farrell and Lily Jan but moved to Washington University before the project was finished. The project was completed by several laboratories.[9][10][11] The cloning and functional expression of a family of voltage-gated K+ channels conserved in all animals brought order to the field of electrophysiology, and validated the use of simple animal models in the field of membrane excitability.[citation needed]

After the initial cloning of the Shaker gene by several laboratories.[9][10][11] Salkoff's laboratory used the Shaker cDNA as a stepping stone [using the technique of low stringency hybridization] with which to clone and functionally characterize the extended gene family of voltage-dependent potassium channels which in addition to Shaker, was designated Shab (Kv2), Shaw (Kv3) and Shal (Kv4).[12] The Salkoff lab then showed that all families were conserved in mammals[12] and were independent current systems (that did not form heteromultimers between families[13] One or more of these genes expressing voltage-dependent potassium currents are expressed in virtually all vertebrate and invertebrate neurons. Salkoff's studies showed that an “essential set” of ion channels was conserved throughout the animal kingdom and was even present in primitive metazoan forms such as jellyfish,[14][15] thus proving that the electrical properties of the nervous system developed early in evolution. This work contributed to one of the fundamental revelations of modern biology, that the basic genes and proteins that form complex animal life are highly conserved, having evolved only once, and presumably present in LUCA, the Last universal common ancestor to all current metazoan life.

In addition to the cloning and characterization of voltage-dependent potassium channels, Salkoff's lab also cloned and functionally characterized the “SLO” family of high conductance potassium channels.[16] The discovery of a high conductance sperm¬specific potassium channel turned out to be the key to understanding membrane potential changes that occur during sperm capacitation; a knockout strain of the SLO3 potassium channel in mouse has turned out to be a valuable tool to investigate membrane potential dependent aspects of sperm physiology.[17]

Honors

Salkoff was the recipient of the “John Belling Prize in Genetics” and was a Research Fellow sponsored by the Muscular Dystrophy Association, the Esther A. and Joseph Klingenstein Fund, Inc.[18] and the National Science Foundation.

Salkoff's published works are available in PubMed and in researchgate

Abstracts of Salkoff's completed and ongoing research projects supported by the National Institutes of Health are available at NIH RePorter

References

  1. ^ "Department of Neuroscience". Department of Neuroscience, Washington University School of Medicine in St. Louis. Retrieved 18 March 2018.
  2. ^ Salkoff, Lawrence; Kelly, Leonard (11 May 1978). "Temperature-induced seizure and frequency-dependent neuromuscular block in a ts mutant of Drosophila". Nature. 273 (5658): 156–8. doi:10.1038/273156a0. PMID 205803. S2CID 4182100.
  3. ^ Hodgkin, A.L.; Huxley, A.F. (August 1952). "A quantitative description of membrane current and its application to conduction and excitation in nerve". J. Physiol. 117 (4): 500–44. doi:10.1113/jphysiol.1952.sp004764. PMC 1392413. PMID 12991237.
  4. ^ Salkoff, L; Wyman, R (October 1, 1980). "Facilitation of membrane electrical excitability in Drosophila". PNAS. 77 (10): 6216–6220. doi:10.1073/pnas.77.10.6216. PMC 350246. PMID 6255482.
  5. ^ Salkoff, L.; Wyman, R. (April 24, 1981). "Outward currents in developing Drosophila flight muscle". Science. 212 (4493): 461–3. doi:10.1126/science.6259736. PMID 6259736.
  6. ^ a b c Salkoff, L.; Wyman, R. (September 17, 1981). "Genetic modification of potassium channels in Drosophila Shaker mutants". Nature. 293 (5829): 228–30. doi:10.1038/293228a0. PMID 6268986. S2CID 4342210.
  7. ^ Salkoff, L (March 17–23, 1983). "Drosophila mutants reveal two components of fast outward current". Nature. 302 (5905): 249–51. doi:10.1038/302249a0. PMID 6300678. S2CID 4274566.
  8. ^ a b c Salkoff, L. (1983). "Genetic and Voltage-clamp Analysis of a Drosophila Potassium Channel". Cold Spring Harbor Symposia on Quantitative Biology. 48 (Pt 1:221–31): 221–231. doi:10.1101/SQB.1983.048.01.025. PMID 6327157. Retrieved 19 March 2018.
  9. ^ a b Papazian, DM; Schwarz, TL; Tempel, BL; Jan, YN; Jan, LY. (Aug 14, 1987). "Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila". Science. 237 (4816): 749–53. doi:10.1126/science.2441470. PMID 2441470.
  10. ^ a b Kamb, A.; Tseng-Crank, J.; Tanouye, MA. (July 1988). "Multiple products of the Drosophila Shaker gene may contribute to potassium channel diversity". Neuron. 1 (5): 421–30. doi:10.1016/0896-6273(88)90192-4. PMID 3272175. S2CID 45304947.
  11. ^ a b Grupe, A; Schröter, KH; Ruppersberg, JP; Stocker, M; Drewes, T; Beckh, S; Pongs, O (June 1990). "Cloning and expression of a human voltage-gated potassium channel. A novel member of the RCK potassium channel family". EMBO Journal. 9 (6): 1749–56. doi:10.1002/j.1460-2075.1990.tb08299.x. PMC 551878. PMID 2347305.
  12. ^ a b Wei, A.; Covarrubias, M.; Butler, A.; Baker, K.; Pak, M.; Salkoff, L. (May 4, 1990). "K+ current diversity is produced by an extended gene family conserved in Drosophila and mouse". Science. 248 (4955): 599–603. doi:10.1126/science.2333511. PMID 2333511.
  13. ^ Covarrubias, M; Wei, AA; Salkoff, L (November 1991). "Shaker, Shal, Shab, and Shaw express independent K+ current systems". Neuron. 7 (5): 763–73. doi:10.1016/0896-6273(91)90279-9. PMID 1742024. S2CID 22841792.
  14. ^ Jegla, T; Grigoriev, N; Gallin, WJ; Salkoff, L; Spencer, AN (December 1995). "Multiple Shaker potassium channels in a primitive metazoan". Journal of Neuroscience. 15 (12): 7989–99. doi:10.1523/JNEUROSCI.15-12-07989.1995. PMC 6577947. PMID 8613736.
  15. ^ Jegla, T.; Salkoff, L. (January 1, 1997). "A novel subunit for shal K+ channels radically alters activation and inactivation". Journal of Neuroscience. 17 (1): 32–44. doi:10.1523/JNEUROSCI.17-01-00032.1997. PMC 6793676. PMID 8987734.
  16. ^ Salkoff, L.; Butler, A.; Ferreira, G.; Santi, C.; Wei, A. (December 2006). "High-conductance potassium channels of the SLO family". Nature Reviews Neuroscience. 7 (12): 921–31. doi:10.1038/nrn1992. PMID 17115074. S2CID 20763845.
  17. ^ Chávez, JC; de la Vega-Beltrán, JL; Escoffier, J; Visconti, PE; Treviño, CL; Darszon, A; Salkoff, L; Santi, CM (April 5, 2013). "Ion permeabilities in mouse sperm reveal an external trigger for SLO3-dependent hyperpolarization". PLOS ONE. 8 (4): e60578. doi:10.1371/journal.pone.0060578. PMC 3618424. PMID 23577126.
  18. ^ "Fellowship Awards in Neuroscience". Klingenstein-Simons. Retrieved 18 March 2018.
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