One area of research, in collaboration with Dr. Nick Penington at SUNY Downstate, is the structure and regulation of TRPC channels, in particular TRPC4 and TRPC5. These channels are widely but differentially expressed in the central nervous system, cardiovascular system, enteric nervous system, GI tract, and other tissues. They are non-selective cation channels involved in Ca2+ signaling and cellular regulation including excitability of neurons and smooth muscle cells. Dysfunction of these channels has been implicated in epilepsy, hypertension, heart failure, and GI motility disorders. Recombinant TRPC channels are studied in model systems, with a focus on regulation by intracellular ATP.
Figure 1. Intracellular ATP inhibits TRPC 5 channels. Currents trough TRPC5 channels activated by carbachol (Carb), acting at M1 muscarinic receptors, were measured in HEK-293 cells in the absence (A) or presence (B) of intracellular ATP. 4 mM ATP almost abolished TRPC5 currents (C). From Dattilo et al., 2008.
A second area of research is the structure, pharmacology, and regulation of NMDA (N-methyl-D-aspartate) receptors and the neuropharmacology of polyamines. These receptors play a crucial role in signaling and synaptic plasticity in the brain, and over-activation of NMDA receptors has been implicated in epilepsy and in neuronal cell death following stroke or traumatic injury. Recombinant NMDA receptors are studied in model systems, with a focus on modulation by endogenous polyamines and atypical antagonists such as ifenprodil.
Figure 2. Modeling the binding pockets for ifenprodil (IFN) and spermine (SPM) on the R domains of the GluN1 and GluN2B subunits of the NMDA receptor. From Tomitori et al., 2012.
Williams, K. (1993). Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol. Pharmacol. 44, 851–859.
Masuko, T., Kashiwagi, K., Kuno, T., Nguyen, N. D., Pahk, A. J., Fukuchi, J., Igarashi, K., and Williams, K. (1999). A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate receptor: effects of spermine, protons, and ifenprodil, and structural similarity to bacterial leucine/isoleucine/valine binding protein. Mol. Pharmacol. 55, 957-969.
Dattilo, M., Penington, N.J., and Williams, K. (2008). Inhibition of TRPC5 channels by intracellular ATP. Mol. Pharmacol. 73, 42–49.
Han, X., Tomitori, H., Mizuno, S., Higashi, K., Full, C., Fukiwake, T., Terui, Y., Leewanich, P., Nishimura, K., Toida, T., Williams, K., Kashiwagi, K., and Igarashi, K. (2008). Binding of spermine and ifenprodil to a purified, soluble regulatory domain of the N-methyl-D-aspartate receptor. J. Neurochem. 107, 1566–1577.
Tomitori, H., Suganami, A., Saiki, R., Mizuno, S., Yoshizawa, Y., Masuko, T., Tamura, Y., Nishimura, K., Toida, T., Williams, K., Kashiwagi, K., and Igarashi, K. (2012). Structural change of R domain heterodimer of NMDA receptor GluN1 and GluN2B through binding of spermine and ifenprodil. J. Pharmacol. Exp. Ther. 343, 82–90.
Hirose, T., Saiki, R, Yoshizawa, Y., Imamura, M., Hihashi, K., Ishii, I., Toida, T., Williams, K., Kashiwagi, K., and Igarashi, K. (2015). Spermidine and Ca2+, but not Na+, can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg2+. Biochem. Biophys. Res. Comm. 463, 1190–1195.
Kashiwagi, K., Williams, K, and Igarashi, K. (2015). Regulation of N-methyl-D-aspartate receptors by spermine and ifenprodil. In: Polyamines: A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism" (T. Kusano and H. Suzuki, eds.), Springer Japan, Chapter 20, 243–253.
Yekaterina Merkuolva, M.D. Ph.D. student (co-advisor with Dr. N. J. Penington)
Editorial board, Molecular Pharmacology (1998-present).
Ad hoc reviewer for various journals and funding agencies.