The laboratory studies the physiology, regulation and biophysics of potassium (K+) channels. These membrane proteins modulate the activity of excitable cells and shape signaling events in non-excitable cells such as hormone and transmitter release. We employ a multidisciplinary approach that integrates techniques such as molecular biology, biochemistry, genetics, optical imaging and electrophysiology. We study K+ channels in two general systems: the genetically tractable worm Caenorhabditis elegans and mammalian heterologous expression systems in which cDNA clones of channels can be studied background-free, under controlled experimental conditions. This approach enables us to bridge in the same organism, genes, proteins, and behavior. We are currently pursuing three areas of research:
Oxidation of K+ channels and neurodegeneration
One theory of aging, the free-radical theory, posits that organisms age because cells accumulate highly reactive, and therefore potentially toxic—molecules known as reactive oxygen species or ROS. Bearing an umpaired electron ROS can oxidize a variety of cellular components causing significant cellular damage. Current projects are aimed at understanding how ROS-mediated oxidation of K+ channels impact the progressive decline in neuronal function which is part of the normal aging process and neurodegenerative disease such as Alzheimer’s.
K+ channels and learning
We recently identified a K+ channel complex, termed KHT-1-MPS-1, homolog to mammalian Kv3.1-KCNE2, which is key to a simple, yet fundamental, form of learning: habituation. Current projects focus on identifying key genes that regulate the expression/trafficking of this channel complex.
A primitive heart model
Mammalian hearts evolved from primitive pumps that appeared more than 500 millions years ago. More recent developments incude peristaltic pumps in Drosophila and in C. elegans (pharynx). We have begun to develop the pharynx of C. elegans into a simple model of the heart. Current projects are aimed at identifying aging genes that protect the function of the pharynx during aging.
Duan Z. and F. Sesti (2015). “Guanine Nucleotide Exchange Factor OSG-1 Confers Functional Aging via Dysregulated Rho Signaling in Caenorhabditis elegans Neurons.” Genetics 199(2):487-96.
Sesti F., Wu X., S. Liu (2014). “Oxidation of KCNB1 K+ channels in central nervous system and beyond” World J Biol Chem 5(2): 85-92.
Iakoubov L., M. Mossakowska, M. Szwed, Z. Duan, F. Sesti, M. Puzianowska-Kuznicka. (2013) "A Common Copy Number Variation (CNV) Polymorphism in the CNTNAP4 Gene: Association with Aging in Females" PLoS ONE 8(11): e79790. doi:10.1371/journal.pone.0079790
Duan Z. and F. Sesti (2013). A Caenorhabditis elegans model system for amylopathy study. JoVE, (75). doi: 10.3791/50435
Swiatkowski P. and F. Sesti (2013) “Delayed pharyngeal repolarization promotes abnormal calcium buildup in aging muscle” Biochem. Biophys. Res. Commun. 433(3): 354-357.
Wu X., Hernandez-Enriquez B., Banas M., Xu R., F. Sesti (2013) “Molecular Mechanisms Underlying the Apoptotic Effect of KCNB1 Oxidation” J. Biol. Chem. 288(6):4128-34.
Cotella D., Hernandez-Enriquez B., Duan Z., Wu X., Gazula VR., Brown MR., Kaczmarek LK. and F. Sesti (2013). “An evolutionarily conserved mode of modulation of Shaw-like K+ channels”. FASEB J, 27(4):271381-93.
Diego Cotella, Berenice Hernandez, Xilong Wu, Ruiqiong Li, Zui Pan, Joseph Leveille, Christopher D. Link, Salvatore Oddo, and F. Sesti (2012). Toxic role of K+ channel oxidation in mammalian brain. J. Neurosci., 32(12):4133-44
F. Sesti, S. Liu and S-Q Cai "Oxidation of K+ channels by ROS: a general mechanism of aging and neurodegeneration?” (2010). Trends in Cell Biology, 20(1):45-51
W. Tutak, M. Chhowalla, F. Sesti (2010). The chemical and physical characteristics of single-walled carbon nanotube film impact on osteoblastic cell response. Nanotechnology, 21 (2010) 315102. Featured in: nanotechweb.org (http://nanotechweb.org/cws/article/lab/43456)
W. Tutak, Ki-Ho Park, G. Fanchini, A. Vasilov, N. Partridge, F. Sesti, M. Chhowalla (2009). Toxicity induced enhanced extracellular matrix production in osteoblastic cells cultured on single walled carbon nanotube networks. Nanotechnology, 20 (2009) 255101.
S-Q. Cai, Y. Wang, K-H. Park, X. Tong, Z. Pan and F. Sesti (2009). Auto-phosphorylation of a voltage-gated K + channel controls non-associative learning. EMBO J. 28(11):1601-10.
S-Q. Cai & F. Sesti (2009). Oxidation of a potassium channel causes progressive sensory function loss during aging. Nature Neurosci., 12(5):611-7. Featured in: Science Signaling, Vol. 2, Issue 69, p. ec152; C&E News (April 13, 2009 Issue); The medical news (http://www.news-medical.net/); Home News Tribune; Faculty of 1000 (biology)
S-Q. Cai, L. Hernandez, Y. Wang, K. H. Park, F. Sesti (2005) “MPS-1 is a K+ channel b-subunit and a serine/threonine kinase” Nature Neurosci. 8(11):1503-9. Featured in: C&E News (March 3, 2008 issue)
A complete list of Dr. Sesti’s publications can be found at: https://scholar.google.com/citations?user=u9_vNPsAAAAJ&hl=en