Electrical signals generated by nerve, skeletal muscle, and heart muscle cells play an essential role in coordination of most physiological functions and in information processing, learning and memory in the central nervous system. Electrical signals are transmitted from cell to cell by synaptic transmission. Research in this laboratory is focused on the voltage-gated sodium and calcium channels, which are responsible for action potential generation in nerve and muscle and for initiation of synaptic transmission and muscle contraction. We study the structure and function of these ion channels, their regulation by physiological pathways, drugs, and neurotoxins, their dysfunction in disease, and their roles in coordination of electrical excitability and synaptic transmission in nerve and muscle cells.
In previous structure-function studies, we developed a molecular map of the functional components of mammalian sodium channels. These studies revealed the sites and molecular mechanisms of voltage-dependent activation, fast inactivation, and ion conduction. Our current studies of the structure and function of sodium and calcium channels have received a great boost from detailed structural modeling using the Rosetta Membrane ab initio modeling system and our determination of the structure of a bacterial ancestor of both sodium and calcium channels at atomic resolution using x-ray crystallography. These new approaches have provided structural models for voltage-dependent activation, slow inactivation, and ion conductance at the atomic level, and they have revealed the detailed mechanism for calcium selectivity and conductance in voltage-gated calcium channels. Current work aims to further define the structural basis for electrical signaling at the atomic level.
Voltage-gated sodium and calcium channels are the molecular targets for drugs that are used to treat pain, epilepsy, cardiac arrhythmia, and hypertension. We have mapped the receptor sites for these drugs on the mammalian sodium and calcium channels proteins, and we are now using our bacterial ancestor of sodium and calcium channels to define the three-dimensional structure of these drug receptor sites at the atomic level. We hope that this work will contribute to structure-based design of new generations of ion channel drugs.
Genetic mutations in sodium channels cause epilepsy, periodic paralysis, cardiac arrhythmia, and other diseases. We study these genetic diseases in order to understand their pathophysiology and provide new approaches to therapy. In addition, we hope that insights into the pathophysiology and therapy of rare genetic syndromes will lead to new insights into the more common, nongenetic forms of these diseases. Our current work in this area is focused on genetic forms of epilepsy and autism.
Regulation of ion channel properties by physiological stimuli is of great interest as a potential mechanism of information processing, learning, and memory in the central nervous system and as a key mechanism for control of other physiological processes. We have studied molecular signaling complexes of sodium and calcium channels that are involved in encoding information in trains of action potentials in neuronal cell bodies and nerve terminals, regulating synaptic function on the millisecond time scale through short-term synaptic plasticity, and controlling the strength of muscle contraction in the fight-or-flight response. This work has identified sites of phosphorylation by specific protein kinases and sites of binding of G protein subunits that modulate sodium and calcium channel function. A presynaptic signaling complex of brain calcium channels with SNARE proteins, protein kinases, and calcium sensor proteins is under investigation in the context of short-term synaptic plasticity, and a signaling complex of cardiac calcium channels with an A Kinase Anchoring Protein that targets cAMP-dependent protein kinase to calcium channels is under investigation in the context of regulation of cardiac contractility in the fight-or-flight response.
Our currently active research projects are described in more detail here.