Catterall, William

Voltage-gated Na channels are responsible for initiation of electrical signaling in nerve, muscle and other excitable cells, and voltage-gated Ca channels are responsible for initiation of synaptic transmission in neurons, excitation-contraction in muscle, secretion in endocrine cells, and many other processes. We have four interests. 1. We study the structure and function of Na channels using structural biology, computational modeling, biochemistry, molecular biology, and electrophysiology. We are interested in how changes in membrane voltage lead to activation and inactivation of these ion channels on the millisecond time scale and how these processes are modified by disease mutations, neurotoxins, drugs, and second-messenger signaling. These studies are guided by our new high-resolution crystal structure of a sodium channel. 2. We study the structure and regulation of voltage-gated Ca channels that initiate synaptic transmission, focusing on their regulation by second messenger pathways and its role in synaptic plasticity, learning, and memory. Current work focuses on the molecular mechanism of short-term synaptic plasticity.  3. We study the structure and regulation of Ca channels that initiate excitation-contraction coupling in skeletal and cardiac muscle and mediate the 'fight-or-flight' response. We have recently reconstituted this regulatory pathway in non-muscle cells for the first time, and we are using this system to analyze the molecular events in this pathway.  4. We study a mouse genetic model of severe myoclonic epilepsy of infancy, which is caused by mutations in brain Na channels. Our goal is to understand the pathophysiology and develop novel therapies for this devastating childhood epilepsy syndrome.