My research interests are targeted at two families of related proteins, the voltage-gated sodium channels and the voltage-gated calcium channels. They are both part of the ion channel superfamily, the members of which are critically important for transmembrane signaling.
Sodium channels are the key proteins underlying the upstroke of the action potential in excitable cells such as neurons, skeletal and cardiac muscle. As such they are responsible for excitability throughout the body. Because of this they are key drug targets for treating pain (local anesthetics), for treating epilepsy (anticonvulsants) and cardiac arrhythmias (antiarrhythmics). Human mutations in these channels have been linked to a broad variety of diseases including cardiac arrhythmias, epilepsies, and muscle paralyses and myotonias.
Calcium channels also underlie electrical activity in a broad range of cells. In addition, calcium entering through these channels acts as an intracellular trigger a wide variety of biological processes including muscle contraction, synaptic transmission, hormone secretion and initiation of gene transcription. Drugs targeting calcium channels are useful in a treating a range of diseases including hypertension and chronic pain. Like sodium channels, mutations in calcium channels have been implicated in human disorders including autism, migraine, ataxia and muscle paralyses.
Both channels are large, multi-component molecular complexes. The central alpha (alpha1 in calcium channels) subunit is a complex protein with multiple functional domains. In addition, each comprises a family with multiple proteins members.
We are interested in many facets of these molecules and their role in biology. Most fundamentally, we are interested in the structure and function of the molecules themselves and how that structure allows them to respond to cell membrane voltage. We are interested in how the channels are blocked by drugs and toxins, both because of the information it provides for making more effective drugs and because the shapes of rigid blocking compounds gives us information about the structure of the channel receptor.Modulation of these channels is fundamental to controlling physiological activity in a broad variety of cells and we are interested in the molecular signaling complexes that support that signaling and the pathways involved. Recently our interests have been increasingly directed to specific roles of these channels in biology and disease. In one project, we study populations of clams chronically exposed to paralytic shellfish toxins released by the dinoflagellates that cause red tides in the ocean. The sodium channels of these clams have responded to the toxin by incorporating amino acid substitutions that make them resistant to the toxins. Disease-related projects target understanding the role of defective sodium channels in epilepsy and muscle myotonias.