James Howe, PhD

Professor Emeritus of Pharmacology

Research Departments & Organizations

Yale School of Medicine

Office of Cooperative Research

Research Interests

Brain; Crystallography, X-Ray; Patch-Clamp Techniques; Pharmacology; Receptors, Glutamate; Synaptic Transmission

Research Summary

We are interested in understanding how the structure of glutamate receptors determines their kinetic behavior. A combination of patch-clamp recording of macroscopic and single-channel currents and X-ray crystallography is employed to elucidate the major conformational changes that translate neurotransmitter binding into ion channel opening and receptor desensitization. Experimental and simulation studies are designed to determine the role of receptor kinetics in shaping synaptic transmission in the brain.

Specialized Terms: Glutamate receptors

Extensive Research Description

Ionotropic glutamate receptors (iGluRs) are protein complexes that form an ion channel in the cell membrane and localize to synapses where they are opened in response to glutamate binding. About 75% of the 100 trillion synaptic connections in the mammalian brain use glutamate-gated ion channels to evoke EPSCs in the postsynaptic cell and human synapses can faithfully follow presynaptic firing at rates of hundreds of action potentials per second. Our lab uses a combination of fast, piezoelectric-controlled, glutamate application to outside-out membrane patches and analysis of data from single receptor molecules to mimic synaptic transmission and study the kinetics of iGluRs.

Over the past decade, often in collaboration with Susumu Tomita (Yale), much of our work has been on modulation of iGluR gating by auxiliary subunits. We showed that the type I TARP stargazin (γ‑2) modulates both ensemble and single-channel currents through AMPARs via protein-protein interactions that depend on its first extracellular domain; showed that the four type I TARPs (Transmembrane AMPA Receptor Proteins) comprise two subfamilies (γ‑2, γ-3 and γ-4, γ-8) which lower the activation energy for channel opening and modulate synaptic currents to different extents. Together with the Tomita lab, we identified the first auxiliary subunit for kainate receptors (Neto2) and showed that it modulated kainate receptor function by slowing entry into desensitization and speeding recovery from it.

Recent work on TARPs demonstrated that TARP modulation of AMPA receptor gating is dynamic and altered by receptor stimulation; the physical interaction of TARPs with pore-forming subunits alters the conformation of the iGluR ligand-binding domain; and TARPs promote a unique gating mode, characterized by long bursts of openings to the largest open levels, that underlies the slow exponential component in the decays of ensemble currents, a feature that is the hallmark of TARP modulation. In addition to our ongoing work with the Tomita lab, we have active collaborations with the laboratories of Vasanthi Jayaraman (UT Houston), Flora Vaccarino (Yale), and Céline Auger (Univ Paris).

Selected Publications

See list of PubMed publications

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