Our major research focus is on understanding the molecular mechanisms through which neuronal excitability is controlled. The lab is particularly interested in how ion channels initiate sensory transduction and control firing threshold. How do these channels regulate signaling and how are they regulated in turn? We are also interested in the structural polarity of neurons, especially in terms of its influence on directional signaling and ion channel distribution. What is unique about our lab is that we take an evolutionary approach to many of our questions: we want to understand how ion channels, neuronal signaling and the structure of neurons themselves evolved.
A new direction in the that capitalizes on our ion channel expertise is studying how plant K+ channels are modulated in guard cells to influence stomatal physiology. Opening and closing of stomata is driven by ion flux, and K+ channels play a role in both processes.
The role of Elk family K+ channels in neuronal signaling: Potassium channels are highly diverse proteins that play key roles in regulating neuronal excitability, from repolarizing action potentials to determining the excitation threshold of neurons to setting neuronal resting potentials. One of the main projects in the lab over the last few years has been characterizing the role of Elk family K+ channels in neuronal signaling. We have shown that Elk channels can contribute significantly to the excitation threshold of neurons, and that loss of Elk channel function leads to neuronal hyperexcitability and seizures in mice. The feature of Elk channels that lets them play this role is that they are active at the neuronal resting potentials when most voltage-gated ion channels are closed. We are studying how the unusual voltage-dependence of Elk channels is regulated by cellular signaling pathways, and studying how Elk channels regulate neuronal physiology in the mammalian nervous system.
The evolution of voltage-gated ion channels: Voltage-gated ion channels regulate the transfer of electrical signals across neurons and thus shape almost all aspects of neuronal signaling. Bilaterian animals (including vertebrates, insects, worms and mollusks) share a large and diverse set of voltage-gated ion channels gene families, each of which plays a unique role in neuronal signaling. We are examining the evolutionary origins of these channel families to determine when and how they evolved in order to gain insights into the functional evolution of the nervous system. Most of our work has focused on voltage-gated K+ channels. The exciting story that is coming out of this work is that many of the types of channels we use to control neuronal signaling are really old, but can’t be traced back to the earliest nervous systems We share a common set of ion channels with the cnidarians (jellyfish, sea anemones, corals and hydra) which diverged from bilaterians more than 600 MYA, but many of our channel families are missing in comb jellies, the most ancient extant animals with nervous systems. We do share a basic core set of channels with comb jellies, but there seems to have been a second major burst of innovation in neuronal signaling in our common ancestor with cnidarians, long after the first nervous systems emerged. In contrast there has been almost no innovation of new channels types in the last 600 MYA, despite dramatic evolution of nervous system complexity! We want to understand what drove the evolution of our voltage-gated ion channels. What did this burst of innovation allow nervous systems to do that they couldn’t do before?
The evolution of neuronal polarity: One reason why our neurons need lost of ion channels is that they are functional polar: signals usually travel from a receptive field of dendrites to the axon, which is the neuron’s output structure. Along the way, we use very distinct types of ion channels to regulate signals in different ways. For instance, axons are specialized to send signals rapidly over distance, while dendrites are specialized to integrate synaptic or sensory inputs into a single output. All bilaterians examined to date have at least some functionally polar neurons with axons and dendrites. However, the evolutionary origins of axons and dendrites have not been determined. We want to know if it was the evolution of neuronal polarity that might have driven the second burst of neuronal ion channel evolution that occurred in the sea anemone/human ancestor. Our hypothesis is that neuronal polarity evolved before our split with cnidarians, but the techniques haven’t previously been available to look for polarity in cnidarian nervous systems. We are now studying the structural polarity of neurons in the sea anemone nerve net using new cell biology and genetic tools to answer this question.
The evolution of TRP channels and sensory perception: TRP channels are a unique class of voltage-gated ion channel that is intimately involved in sensory perception. TRP channels convert stimuli as diverse as light, heat, cold and touch into electrical signals that can be transferred across neurons. We are examining the evolution of TRP channels and sensory perception using our sea anemone model.
Activation of TRPC3 by melanopsin at various wavelengths
The evolution of behavior: One of our long term goals is to understand how the evolution of neuronal signaling at the level of ion channels and neuronal polarity influenced the evolution of behavior. We want to characterize the molecular and cellular basis of evolutionarily behavioral pathways using our sea anemone model.
Modulation of voltage-gating in plant guard cell K+ channels: Opening and closing of stomata in plant leaves is driven by turgor pressure changes in guard cells. Guard cells therefore play a key role in optimizing the balance between gas uptake for photosynthesis and water loss. Increasing guard cell turgor driven by ion uptake opens stomata while decreasing turgor through ion influx closes the stomata. Inwardly rectifying K+ channels that drive K+ influx facilitate opening, while outwardly rectifying K+ channels that drive K+ efflux help drive closing. We are studying how the voltage sensitivity of these channels is modulated by physiological factors to effect changes in stomatal tone.