Physiology and Biophysics


William Zagotta Ph.D.


Ph.D. Neuroscience
Stanford University, 1989

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Molecular Mechanisms of Ion Channel Function

Ion channel proteins are the fundamental molecular elements for the control of membrane excitability and signaling in the nervous system. In response to one or more of a variety of stimuli, including neurotransmitters, voltage, and internal second messengers, ion channels open and allow the passage of certain selected ions across the cell membrane. In this way, channels can transduce these stimuli into changes in membrane potential and/or intracellular levels of calcium, the signals most used by the nervous system. The properties of each ion channel are highly specialized for its particular function. To this end, our long term goal is to determine the molecular mechanisms of the opening and closing conformational changes in ion channels. We have focused on a family of channels that is regulated by the direct binding of cyclic nucleotides, cAMP and cGMP. These channels play a fundamental role in the initial generation of an electrical signal in sensory receptors such as photoreceptors and olfactory receptors, and in the control of the pacemaker activity in cardiac and neuronal cells. To study the mechanism of gating by cyclic nucleotides, we employ a variety of approaches including electrophysiology, site-directed mutagenesis, protein chemistry, site-specific fluorescent labeling, and X-ray crystallography. By the combination of these approaches we believe we will be able to gain new insights into the molecular mechanisms for channel function.