Many cells respond to extracellular molecules by means of chemically activated ion channels in their cell membrane. In the nervous system transmitter-activated channels underlie rapid synaptic transmission. The goal of work in my lab is to determine how transmitter-gated channels are activated and how cells control the way in which their chemically activated channels function.
This research involves biophysical techniques to measure membrane currents (voltage clamp and single channel recordings) and biochemical studies of receptor structure and pharmacology. Experiments are performed using cultured cells so the structure of the channel can be modified by expression of defined subunits (either normal or mutated), or by manipulation of posttranslational modifications. The data are analyzed to provide estimates of transmitter affinities and channel opening and closing rates. The mechanism of action for drugs which inhibit or modulate channel activation is examined, using the same approaches. My work involves studies of three members of an extended gene family — the nicotinic receptor, the GABA-A receptor and the glycine receptor. We generate cell lines that stably express recombinant receptor proteins, as well as use transient expression of mutated subunits to explore the relationship between channel structure and the action of drugs on the receptors. The results are used to increase our understanding of quantitative aspects of synaptic transmission, in normal or pathological states. They also give insights into actions of clinically used drugs, including muscle relaxants, general anesthetics and sedative-hypnotic drugs.