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Biological Sciences Department Faculty
Joan L. and Julius H. Professor of Biomedical Research
Distinguished University Professor
Ph.D., University of Massachusetts, 1976
M.S., University of Massachusetts, 1973
B.A., Holy Cross, 1971
Monoamines, such as serotonin (5-HT), regulate diverse central and peripheral responses, including circadian rhythms, mood, perception and aggression and a variety of drugs modulate aminergic signaling in the treatment of schizophrenia, depression, ADHD, obesity and migraine. Clearly, changes in aminergic signaling can have profound effects on behavior. In parasitic nematodes, monoamines modulate key drug targets, such as feeding and locomotion. We have identified and characterized a number of monoamine receptors that modulate simple, sensory-mediated, locomotory behaviors in the free-living nematode Caenorhabditis elegans, not only to identify potential targets for anthelminthic development, but also to better understand the aminergic modulation of human behavior. Research is divided into two areas:
Identifying new targets for anthelminthic development: Parasitic nematodes cause billions of dollars of damage yearly to crops (soybeans, corn), livestock (sheep, cattle) and humans worldwide. Unfortunately, pharmaceuticals designed to control these infections are limited and even in cases where effective chemotherapy has been developed, resistance is an ever-increasing problem. Therefore, the continued identification of novel anthelminthics is essential. A major focus of the laboratory is the identification of targets for chemotherapy to control a variety of nematode infections of both veterinary and medical importance. Many effective anthelminthics inhibit muscle contraction by either inhibiting energy metabolism or interfering with processes at the neuromuscular junction. However, the development of high throughput screens has been hindered by the lack of useful molecular information about the structure, function and localization of potential targets. While the ultimate goal of our group is the development of effective chemotherapy, much of our current work involves understanding the regulation of nematode muscle contraction and energy-generation, using both the porcine parasitic nematode, Ascaris suum and C. elegans as models. Current projects focus on the role of monoamines and peptides in the modulation of both feeding (pharyngeal pumping) and locomotion.
C. elegans as a model for depression: The brain is composed of billions of neurons with trillions of connections that form an intricate communication network. The wonder of human consciousness emerges from this mind-boggling complexity, but unfortunately, when disease or injury strikes the nervous system, the results can be particularly debilitating. In fact, most drug therapies for nervous system disorders modify neuronal signaling in some way. Here, at The University of Toledo, we have assembled a multi-investigator team to study a much simpler organism, C. elegans, as a model for human disease. This tiny worm has only 302 neurons and its synaptic connectivities have been mapped almost completely, allowing us to examine neuronal signaling in a simple system and avoid tackling the overwhelming complexity of the human brain directly. Remarkably, neuronal development and communication are similar in all organisms and, in most cases, C. elegans uses the same set of signaling molecules as its vertebrate counterparts. Neuronal signaling in the worm is, therefore, a useful model for neuronal signaling and neuronal dysfunction in humans, despite the vast differences in size and complexity. Indeed, many of the key signaling molecules in humans were first identified in simple model systems and many pharmaceuticals, such as the antidepressant Prozac, have similar modes of action in nematodes. We have begun to dissect a number of simple monoamine-mediated C. elegans olfactory circuits at the molecular level with the strong belief that this approach will provide insights into the more complex aminergic circuits operating in the humans. Current projects focus of the role and downstream signaling of aminergic and peptidergic receptors in the modulation of a variety of sensory mediated locomotory behaviors.
Xiao, H., Hapiak, V., Smith, K., Lin, L., Hobson, R., Plenefisch, J. and Komuniecki, R. 2006. The interaction of a 5-HT2-like receptor (SER-1) and a multi-PDZ domain containing protein, MPZ-1, in vulval muscle optimizes serotonin stimulated egg-laying in Caenorhabditis elegans. Dev. Biol. 298, 379-391.
Smith, K., Rex, E., and Komuniecki, R. 2007. Are C. elegans receptors useful targets for drug discovery: Pharmacological comparison of tyramine receptors with high identity from Caenorhabditis elegans (TYRA-2) and Brugia malayi (Bm4). Mol. Biochem. Parasitol. 154, 52-61.
Ghedin, E. , Wang, S., Spiro, D., Caler, E., Zhao, Q., Crabtree, J., Allen, J., Delcher, A., Guiliano, D.,Miranda-Saavedra, D., Angiuoli, S., Creasy, T., Amedeo, P., Haas, B., El-Sayed, N., Wortman, J., Feldblyum, T., Tallon, L., Schatz M., Shumway M., Koo, H., Salzberg, S., Schobel, S., Pop, M., White, O., Barton, G., Carlow, C., Crawford, M., Daub, J., Dimmic, M., Estes, C., Foster, J., Ganatra, M., Gregory, W., Johnson, N., Jin, J., Komuniecki, R., Korf, I., Kumar, S., Laney, S., Li, B., Li, W., Lindblom, T., Lustigman, S., Ma, D., Maina, C., Martin, D., McCarter, J., McReynolds, L., Mitreva, M., Nutman, T., Parkinson, J., Peregrín-Alvarez, J., Poole, C., Ren, Q., Saunders, L., Sluder, A., Smith, K., Stanke, M., Unnasch, T., Ware, J., Wei, A., Weil, G., Williams, D., Zhang, Y., Williams, S., Fraser-Liggett C., Slatko, B., Blaxter, M., and Scott, A. 2007. . The genome of the filarial nematode parasite, Brugia malayi 2007. Science 317,1756-60.
Wragg, R., Hapiak, V., Miller, S., Harris, G., Gray, J., Komuniecki P.R. and Komuniecki, R. 2007. Tyramine and octopamine independently inhibit serotonin-stimulated aversive behaviors in Caenorhabditis elegans through two novel amine receptors. J. Neuroscience 27, 13402-12.
Smith, K., Komuniecki, R., Ghedin, E., Spiro, D., and Gray, J. 2007. Genes encoding putative biogenic amine receptors in the parasitic nematode, Brugia malayi. Invertebrate Neuroscience 7, 227-44.
Harris, G., Hapiak, V.,Wragg, R., Miller, S.,Smith1, K., Hughes, L., Hobson, R., Steven R., Bamber, B. and Komuniecki, R. 2009. Three distinct amine receptors operating a different levels within the locomotory circuit are each essential for the serotonergic modulation of chemosensation in Caenorhabditis elegans. J. Neuroscience 29, 1446-1456.
Hapiak, V., Hobson, R., Hughes, L., Smith, K., Harris, G., Condon, C., Komuniecki, P. and Komuniecki R. 2009. Dual excitatory and inhibitory serotonergic inputs modulate egg-laying in Caenorhabditis elegans. Genetics 181, 153-163.
Harris, G., Mills, H., Wragg, R., Hapiak, V., Castelletto, M., Korchnak, A. and Komuniecki, R.W. 2010. The monoaminergic modulation of sensory-mediated aversive responses in Caenorhabditis elegans requires glutamatergic/peptidergic cotransmission. J. Neuroscience 23:7889-99.
Kullyev, A., Dempsey, C.M., Miller, S., Kuan, C.J., Hapiak, V.M., Komunieck,i R.W., Griffin, C.T. and Sze J.Y. 2010. A genetic survey of fluoxetine action on synaptic transmission in Caenorhabditis elegans. Genetics 186, 929-41.
Harris G., Korchnak A., Summers P., Hapiak V., Law W.J., Stein A.M., Komuniecki P. and Komuniecki R. 2011. Dissecting the serotonergic food signal stimulating sensory-mediated aversive behavior in C. elegans. PLoS One 7:e21897.
Mills, H., Wragg, R., Hapiak, V., Castelletto, M., Zahratka, J., Harris, G., Summer. P., Korchnak, Law, W., Bamber, B. and Komuniecki, R.W. 2011. Monoamines and neuropeptides interact to inhibit aversive behavior in Caenorhabditis elegans. EMBO J. 31, 667-678.
Komuniecki R., Harris G., Hapiak V.., Wragg R, Bamber B. 2011. Monoamines activate neuropeptide signaling cascades to modulate nociception in C. elegans: a useful model for the modulation of chronic pain? Invert Neurosci. PMID: 22143253
Komuniecki R., Law W.J., Jex A., Geldhof P., Gray J., Bamber B., Gasser R.B. 2012. Monoaminergic signaling as a target for anthelmintic drug discovery: Receptor conservation among the free-living and parasitic nematodes. Mol Biochem Parasitol. 183, 1-7.