Regulation of TRPC Channels and NMDA Receptors
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
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.
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.