Research Expertise and Interest

Ion channel function, synaptic plasticity, neural excitability, synaptic transmission, the synapse

Research Description

The work in the lab is focused on ion channels and other signaling proteins, and their role in neural excitability, synaptic transmission, and the molecular and functional development of the synapse.

Current Projects

Structure and protein motions of voltage and ligand gated channels. We have developed new methods for studying ion channel structure and protein motion. We label channel proteins on the surface of living cells in a site-directed manner with fluorescent dyes. We detect local protein motion via changes in the microenvironment of the dye in real-time, with sub-millisecond resolution, by measuring fluorescence intensity, wavelength and dye mobility. These optical reports identify "what moves when" in relation to functional events that are synchronized for the channel population and measured with a voltage clamp. In addition to obtaining kinetic maps of protein motion, we use fluorescence resonance energy transfer as a spectroscopic ruler to make structural determinations. This method enables us to view movements of individual segments of the channel protein, in individual subunits, so that the spatial location and role in gating of each domain of the protein can be determined. From measurements of movement and distance we are working to assemble an animated structural model of the conformational rearrangements that activate, open, close and inactivate channels. In addition, we are now beginning to make optical measurements of protein motion on the single channel level. Our work, which began with a voltage-gated K+ channel, is now expanding to other classes of channels that are activated by very different classes of signals, such as ligand binding. Our aim is to discover general principles that enable different kinds of signal transduction apparatus to control the conformation of molecular gates that control ion flux and ion selectivity.

Development of genetically encoded optical sensors of cell signaling. Measuring electrical activity in large numbers of cells with high spatial and temporal resolution is a fundamental problem for the study of neural signaling. To address this problem, we have constructed a novel, genetically-encoded probe that can be used to measure transmembrane voltage in single cells. We fused a modified green fluorescent protein (GFP) into the voltage-sensitive Shaker channel, creating a channel whose voltage-dependent rearrangements induce large changes in the fluorescence of GFP. A genetically manipulable voltage sensor has the advantage that its operating range can be tuned by mutagenesis, and that it may be introduced into an organism and targeted for expression to specific developmental stages, brain regions, cell types, and sub-cellular locations. We are using similar strategies to develop different optical sensors by fusing this GFP to other detector proteins such as channels and receptors. Such sensors can be used to ask specific biological questions about the native role of the detector proteins, or, instead, to report on the signals that activate these proteins. We are using such sensors to determine the role of signaling pathways in Drosophila synapse formation and in several other model synaptic systems.

In the News

Weill Neurohub will fuel race to find new treatments for brain disease

With a $106 million gift from the Weill Family Foundation, UC Berkeley (Berkeley), UC San Francisco (UCSF) and the University of Washington (the UW) have launched the Weill Neurohub, an innovative research network that will forge and nurture new collaborations between neuroscientists and researchers working in an array of other disciplines—including engineering, computer science, physics, chemistry, and mathematics—to speed the development of new therapies for diseases and disorders that affect the brain and nervous system.

With single gene insertion, blind mice regain sight

University of California, Berkeley, scientists inserted a gene for a green-light receptor into the eyes of blind mice and, a month later, they were navigating around obstacles as easily as mice with no vision problems. The researchers say that, within as little as three years, the gene therapy — delivered via an inactivated virus — could be tried in humans who’ve lost sight because of retinal degeneration, ideally giving them enough vision to move around and potentially restoring their ability to read or watch video.

New therapy holds promise for restoring vision

A new genetic therapy developed by UC Berkeley scientists has not only helped blind mice regain light sensitivity sufficient to distinguish flashing from non-flashing lights, but also restored light response to the retinas of dogs, setting the stage for future clinical trials of the therapy in humans. The therapy involves inserting photoswitches into retinal cells that are normally ‘blind.’

On Memory’s Trail

Ehud Isacoff and his colleagues explore the brain at several levels critical to ultimately understand how memories form and what can threaten their demise. He is the Director of Berkeley’s Helen Wills Neuroscience Institute.

Neural circuit ensures zebrafish will not bite off more than it can chew

UC Berkeley neuroscientists have found that when zebrafish larvae see large objects, like leaves or other zebrafish, inhibitory nerve cells fire in the brain to tamp down a prey response. But when the larvae see small, prey-size objects, fewer inhibitory nerve cells fire and the fish quickly responds. This simple neural circuit helps explain the visual filters that enable prey capture.

Featured in the Media

Please note: The views and opinions expressed in these articles are those of the authors and do not necessarily reflect the official policy or positions of UC Berkeley.
March 18, 2019
Michael McGough
Using a new and relatively simple gene-therapy treatment, Berkeley scientists have restored enough sight in previously blind mice that within a month they were navigating their environment with the same ease as sighted mice. The treatment involved just one injection of a gene for a green-light receptor into the eyes. "With neurodegenerative diseases of the retina, often all people try to do is halt or slow further degeneration," says molecular and cell biology professor Ehud Isacoff, director of the Helen Wills Neuroscience Institute and one of the study's co-authors. "But something that restores an image in a few months -- it is an amazing thing to think about." The findings offer hope to roughly 170 million people around the world with age-related macular degeneration, and 1.7 million people with a common form of inherited blindness, called retinitis pigmentosa. The team is now raising money to begin human trials in the next three years. For more on this, see our press release at Berkeley News. Stories on this topic have appeared in dozens of sources, including the San Francisco Chronicle Online and Interesting Engineering.
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