Research & Projects

Glutamate-gated ion channels

Neural plasticity is among the most important and intriguing properties of the central nervous system, underlying our ability to adapt and respond to experience. Learning and memory, addiction, and post-traumatic stress disorder are all manifestations of neural plasticity, each driven by different types of experiences.

The molecular events underlying neural plasticity originate at the level of synapses and hinge on a family of glutamate-gated ion channels called AMPA receptors. These transmembrane receptors mediate the fast synaptic transmission between excitatory neurons and activity-driven changes in the structure and function of AMPA receptors and provide a primary mechanism for information storage in the mammalian brain. Developing compounds that effectively track these changes in AMPA receptors is a particularly challenging goal because neuronal activity can induce changes in the number, subtype, phosphorylation state, and/or association with auxiliary subunits of AMPA receptors.

Previously, the England Lab developed a photoreactive AMPA receptor antagonist (ANQX) that provided a means of monitoring the trafficking of AMPA receptors in real time.

Currently the laboratory is focused on developing subtype-selective ligands for AMPA receptors. Multiple AMPA receptor subtypes are expressed on neurons and considerable evidence suggests that activity-dependent changes in the specific subtypes present at synapses (subtype-switching) is an essential aspect of neural plasticity. Successful development of subtype-selective ligands for AMPA receptors will advance our understanding of the mechanisms underlying neural plasticity and enable proof-of-principle studies linking individual AMPA receptor subtypes to specific cognitive outcomes.

Experience drives changes in the frequency at which action potentials are fired by neurons, which in turn cause fluctuations in the release of glutamate at synapses. These fluctuations induce changes in the functional state of synaptic AMPA receptors (e.g., number, subtype, phosphorylation). The information encoded in these changes underlies many adaptive functions, including several forms of learning and memory.

Nuclear receptors

Nuclear receptors are structural chameleons, selectively interacting with different protein partners depending on the bound ligand. These interactions determine the transcriptional profile of a cell.

Nuclear receptors are a class of intracellular proteins responsible for sensing steroid and thyroid hormones and certain other small lipophilic molecules, and in response, regulating gene expression. These receptors play a role in every aspect of development, physiology, and disease in humans. Ligand binding to nuclear receptors drives an allosteric reformation of protein interaction surfaces on the receptor. These interaction surfaces attach to a variety of regulatory proteins to form complexes that enter the nucleus and drive transcription. The structure of the bound ligand determines which protein partners the receptor interacts with and, thus, the transcriptional profile of the cell.

Developing compounds that effectively control the activities of nuclear receptors is a particularly challenging goal because, aside from very few critical polar atom interactions between the ligand and the receptor, the ligand-occupied pocket is a dynamic, flexible globular cluster of nonpolar atoms. It is this cluster that reforms the interaction surfaces of the receptor and determines its partnerships in macromolecular interactions. The England Lab is developing ligands that regulate the formation of specific nuclear receptor-protein complexes to control gene transcription. The approach we use precisely controls the position, orientation, and interaction of the ligand within the receptor’s binding pocket by covalently tethering the ligand to the receptor. The rational addition of chemical “bumps” to the covalent ligand is used to drive defined changes in the protein interaction surfaces on the receptor. In this way, bound ligands are used to control the formation of specific nuclear receptor-protein complexes and, thus, the fates of cells.