Potentiation of Glycine Receptor Channels by General Anesthetics
James P. Dilger, PhD

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he current research in Dr. Dilger’s laboratory is focused on mechanisms of action of general anesthetics on synaptic ion channels. General anesthetics such as propofol and isoflurane potentiate inhibitory synaptic channels such as the strychnine-sensitive glycine receptor. Dr. Dilger uses patch clamp electrophysiological techniques to record the currents that flow through ion channels in the cell membrane. His lab pioneered the development of methods for rapid (less than 1 millisecond) concentration jumps that mimic conditions at a fast synapse. Both macroscopic and single channel currents are used in these investigations. The overall goals are a) to understand how the binding of glycine to the receptor causes the channel gate to open and b) to understand how general anesthetics cause this gating to be more efficient.

insert research data or photo A recent project from the Dilger Lab examined how different muscle relaxants bind to each of the two distinct ligand binding sites on the muscle acetylcholine receptor. Most benzylisoquinolines, such as (+)-tubocurarine have higher affinity for the site at the α-ε subunit interface while most aminosteroids, such as pancuronium, have higher affinity for the site at the α-δ subunit interface. The cartoon illustrates the binding of curare (left) and pancuronium (right) to different interfacial binding sites on the adult muscle acetylcholine receptor. This may be part of the reason that some combinations of muscle relaxants are synergistic. (Liu & Dilger, Anesth Analg. 2008 Aug;107(2):525)



  Another project employs a Monte Carlo simulation program (MCell) to model the behavior of biological synapses. Here, we compared the diffusion of a reversible antagonist (A) with an irreversible antagonist (B) into a narrow synaptic cleft containing a high density of receptors. Antagonist-bound receptors are red, antagonist-free receptors are green. The different patterns of receptor occupancy may help explain why reversible ACh receptor antagonists such as curare, cause fade at the neuromuscular junction but irreversible antagonists such as αBTX do not. (Dilger, Biophys J. 2010, 98:595). Movie

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