Ionotropic Glutamate Receptors
The functioning of the brain relies on transmission of information between its cellular elements, neurons. Signals from one neuron to another travel through contact zones called synapses. Neurotransmission through a synapse involves arrival of the action potential to the presynaptic terminal, release of a neurotransmitter to the synaptic cleft and binding of the neurotransmitter to and activation of postsynaptic receptors. The activated postsynaptic receptors open their channel pores for ion conductance, leading to changes in the postsynaptic membrane potential and triggering an action potential in the postsynaptic neuron that travels down the neuronal network. The key players of this electro-chemical signaling are postsynaptic receptors. Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission and are activated by the neurotransmitter glutamate. The fastest subtype of iGluRs, AMPA receptors (AMPARs), do not reside in the postsynaptic membrane alone but are surrounded by numerous auxiliary subunits, thus representing a core of synaptic complexes. Being the integral components of synaptic complexes, auxiliary subunits regulate AMPAR trafficking, localization, and function, determine synaptic strength and plasticity, and, as a result, modulate high cognitive brain functions, such as learning and memory. We have been studying how different auxiliary subunits regulate AMPAR function using biophysical and biochemical techniques, including but not limited to cryo-electron microscopy (cryo-EM), X-ray crystallography, kinetic modeling, and electrophysiology approaches.
Transient Receptor Potential Channels
Transient Receptor Potential (TRP) channels are a superfamily of ~28 different ion channels. Some TRP channels gate in response to heat, cold, mechanical force, and/or pungent chemicals, implicating these channels as molecular «sensors» of environmental cues. In addition, TRP channels play important roles in a wide variety of other physiological processes, including calcium homeostasis, neurite outgrowth, and hormone secretion. TRPV6 (pictured above) is a channel found in gut cells that captures calcium ions from the diet. Mutations or changes in TRPV6 gene expression are linked to several cancers and other diseases including hyperparathyroidism, metabolic bone disease, chronic pancreatitis, and kidney stone formation. Advances in structural biology, particularly the “resolution revolution” in cryo-EM, have led to breakthroughs in molecular characterization of TRPV channels. Structures with continuously improving resolution uncover atomic details of TRPV channel interactions with small molecules and protein-binding partners. The characterized binding sites and molecular mechanisms of ligand action create a diversity of druggable targets to aid in the design of new molecules for tuning TRP channel function in disease conditions. We aim to examine TRP channel structure-function mechanisms using a range of biochemical and biophysical approaches, including X-ray crystallography, cryo-EM, and electrophysiology.
Picture above is from review article from our lab — «Ligand-Binding Sites in Vanilloid-Subtype TRP Channels» published in Frontiers of Pharmacology.
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