L. Keith Henry

RESEARCH

In my lab, we use of pharmacology, biochemistry, computational, epigenetic and evolutionary methods to understand the physiological role of the sertotonin (SERT) and dopamine (DAT) transporters and their role in human health and disease. The scope of our studies spans from molecules to whole organisms.

Depression and Drug Abuse

SERT and DAT are inhibited by compounds such as antidepressants and drugs of abuse such as cocaine, amphetamine and ecstasy. We are studying how these clinically important drugs and other atypical drugs interact with the transporters at the molecular level.  This work has the potential to lead to real advances in novel drug development and pharmacological interventions.

Autism and SERT

Single nucleotide polymorphisms in human SERT have been shown to elevate transport function and have been linked to behavioral aspects of Autism Spectrum Disorder. We are working to uncover the molecular mechanisms behind the effects of these mutations.

Epigenetic Programming by Antidepressants

In addition to being a neurotransmitter, serotonin is a important molecule in animal development. As such, we are interested in that possibility that antidepressants can have epigenetic implications on anxiety, depression and other mood disorders.

1. Simmler, L. D., Anacker, A. M. J., Levin, M. H., Vaswani, N. M., Gresch, P. J., Nackenoff, A. G., Anastasio, N. C., Stutz, S. J., Cunningham, K. A., Wang, J., Zhang, B., Henry, L. K., Stewart, A., Veenstra-VanderWeele, J., and Blakely, R. D. (2017) Blockade of the 5-HT transporter contributes to the behavioral, neuronal and molecular effects of cocaine. Br. J. Pharmacol. 174, 2716–2738
   
   
2. Krout, D., Pramod, A. B., Dahal, R. A., Tomlinson, M. J., Sharma, B., Foster, J. D., Zou, M.-F., Boatang, C., Newman, A. H., Lever, J. R., Vaughan, R. A., and Henry, L. K. (2017) Inhibitor mechanisms in the S1 binding site of the dopamine transporter defined by multi-site molecular tethering of photoactive cocaine analogs. Biochem. Pharmacol. 10.1016/j.bcp.2017.07.015
   
   
3. Krout, D., Rodriquez, M., Brose, S. A., Golovko, M. Y., Henry, L. K., and Thompson, B. J. (2017) Inhibition of the Serotonin Transporter Is Altered by Metabolites of Selective Serotonin and Norepinephrine Reuptake Inhibitors and Represents a Caution to Acute or Chronic Treatment Paradigms. ACS Chem. Neurosci. 8, 1011–1018
   
   
4. Sealover, N. R., Felts, B., Kuntz, C. P., Jarrard, R. E., Hockerman, G. H., Barker, E. L., and Henry, L. K. (2016) The external gate of the human and Drosophila serotonin transporters requires a basic/acidic amino acid pair for 3,4-methylenedioxymethamphetamine (MDMA) translocation and the induction of substrate efflux. Biochem. Pharmacol. 120, 46–55
   
   
5. Richardson, B. D., Saha, K., Krout, D., Cabrera, E., Felts, B., Henry, L. K., Swant, J., Zou, M.-F., Newman, A. H., and Khoshbouei, H. (2016) Membrane potential shapes regulation of dopamine transporter trafficking at the plasma membrane. Nat. Commun. 7, 10423
   
   
6. Kumar, V., Yarravarapu, N., Lapinsky, D. J., Perley, D., Felts, B., Tomlinson, M. J., Vaughan, R. A., Henry, L. K., Lever, J. R., and Newman, A. H. (2015) Novel Azido-Iodo Photoaffinity Ligands for the Human Serotonin Transporter Based on the Selective Serotonin Reuptake Inhibitor (S)-Citalopram. J. Med. Chem. 58, 5609–5619
   
   
7. Dahal, R. A., Pramod, A. B., Sharma, B., Krout, D., Foster, J. D., Cha, J. H., Cao, J., Newman, A. H., Lever, J. R., Vaughan, R. A., and Henry, L. K. (2014) Computational and biochemical docking of the irreversible cocaine analog RTI 82 directly demonstrates ligand positioning in the dopamine transporter central substrate-binding site. J. Biol. Chem. 289, 29712–29727
   
   
8. Bowton, E., Saunders, C., Reddy, I. A., Campbell, N. G., Hamilton, P. J., Henry, L. K., Coon, H., Sakrikar, D., Veenstra-VanderWeele, J. M., Blakely, R. D., Sutcliffe, J., Matthies, H. J. G., Erreger, K., and Galli, A. (2014) SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking. Transl. Psychiatry. 4, e464
   
   
9. Gaffaney, J. D., Shetty, M., Felts, B., Pramod, A.-B., Foster, J. D., Henry, L. K., and Vaughan, R. A. (2014) Antagonist-induced conformational changes in dopamine transporter extracellular loop two involve residues in a potential salt bridge. Neurochem. Int. 73, 16–26
   
   
10. Beckman, M. L., Pramod, A. B., Perley, D., and Henry, L. K. (2014) Stereoselective inhibition of serotonin transporters by antimalarial compounds. Neurochem. Int. 73, 98–106
    
    
11. Felts, B., Pramod, A. B., Sandtner, W., Burbach, N., Bulling, S., Sitte, H. H., and Henry, L. K. (2014) The two Na+ sites in the human serotonin transporter play distinct roles in the ion coupling and electrogenicity of transport. J. Biol. Chem. 289, 1825–1840
    
    
12. Pramod, A. B., Foster, J., Carvelli, L., and Henry, L. K. (2013) SLC6 transporters: structure, function, regulation, disease association and therapeutics. Mol. Aspects Med. 34, 197–219
    
    
13. Henry, L. K., Iwamoto, H., Field, J. R., Kaufmann, K., Dawson, E. S., Jacobs, M. T., Adams, C., Felts, B., Zdravkovic, I., Armstrong, V., Combs, S., Solis, E., Rudnick, G., Noskov, S. Y., DeFelice, L. J., Meiler, J., and Blakely, R. D. (2011) A conserved asparagine residue in transmembrane segment 1 (TM1) of serotonin transporter dictates chloride-coupled neurotransmitter transport. J. Biol. Chem. 286, 30823–30836
    
    
14. Thompson, B. J., Jessen, T., Henry, L. K., Field, J. R., Gamble, K. L., Gresch, P. J., Carneiro, A. M., Horton, R. E., Chisnell, P. J., Belova, Y., McMahon, D. G., Daws, L. C., and Blakely, R. D. (2011) Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter. Proc. Natl. Acad. Sci. U. S. A. 108, 3785–3790
    
    
15. Field, J. R., Henry, L. K., and Blakely, R. D. (2010) Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4-methylene dioxymethamphetamine. J. Biol. Chem. 285, 11270–11280
    
    
16. Kaufmann, K. W., Dawson, E. S., Henry, L. K., Field, J. R., Blakely, R. D., and Meiler, J. (2009) Structural determinants of species-selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies. Proteins. 74, 630–642
    
    
17. Henry, L. K., and Blakely, R. D. (2008) Distinctions between dopamine transporter antagonists could be just around the bend. Mol. Pharmacol. 73, 616–618
    
    
18. Henry, L. K., Meiler, J., and Blakely, R. D. (2007) Bound to be different: neurotransmitter transporters meet their bacterial cousins. Mol. Interv. 7, 306–309
    
    
19. Henry, L. K., DeFelice, L. J., and Blakely, R. D. (2006) Getting the message across: a recent transporter structure shows the way. Neuron. 49, 791–796
    
    
20. Henry, L. K., Field, J. R., Adkins, E. M., Parnas, M. L., Vaughan, R. A., Zou, M.-F., Newman, A. H., and Blakely, R. D. (2006) Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants. J. Biol. Chem. 281, 2012–2023
    
    
21. Henry, L. K., Adkins, E. M., Han, Q., and Blakely, R. D. (2003) Serotonin and cocaine-sensitive inactivation of human serotonin transporters by methanethiosulfonates targeted to transmembrane domain I. J. Biol. Chem. 278, 37052–37063
    
    
22. Henry, L. K., Khare, S., Son, C., Babu, V. V. S., Naider, F., and Becker, J. M. (2002) Identification of a contact region between the tridecapeptide alpha-factor mating pheromone of Saccharomyces cerevisiae and its G protein-coupled receptor by photoaffinity labeling. Biochemistry. 41, 6128–6139
    
    
23. Liu, S., Henry, L. K., Lee, B. K., Wang, S. H., Arshava, B., Becker, J. M., and Naider, F. (2000) Position 13 analogs of the tridecapeptide mating pheromone from Saccharomyces cerevisiae: design of an iodinatable ligand for receptor binding. J. Pept. Res. 56, 24–34
    
    
24. Lay, J., Henry, L. K., Clifford, J., Koltin, Y., Bulawa, C. E., and Becker, J. M. (1998) Altered expression of selectable marker URA3 in gene-disrupted Candida albicans strains complicates interpretation of virulence studies. Infect. Immun. 66, 5301–5306
    
    
25. Bulawa, C. E., Miller, D. W., Henry, L. K., and Becker, J. M. (1995) Attenuated virulence of chitin-deficient mutants of Candida albicans. Proc. Natl. Acad. Sci. U. S. A. 92, 10570–10574
    
    
26. Becker, J. M., Henry, L. K., Jiang, W., and Koltin, Y. (1995) Reduced virulence of Candida albicans mutants affected in multidrug resistance. Infect. Immun. 63, 4515–4518

Vanderbilt University: Nashville, Tennessee
Faculty Instructor in the Department of Pharmacology

Vanderbilt University: Nashville, Tennessee
Postdoctoral Fellow in the Department of Pharmacology

The University of Tennessee: Knoxville, Tennessee
Doctoral Degree in Cellular, Molecular and Developmental Biology

The University of Tennessee: Knoxville, Tennessee
B.S. in Cell Biology, May 1992