Graduate Training in Neuroscience
University of Washington
William A. Catterall
Professor and Chair, Department of Pharmacology
The Molecular Basis of Electrical Excitability
Electrical impulses generated by nerve, skeletal muscle, and heart muscle cells play an essential role in coordination of most physiological functions and in learning and memory in the central nervous system. Research in this laboratory is focused on understanding the molecular basis of electrical excitability, the regulation of electrical excitability by physiological stimuli, and the mechanism of action of neurotoxins and drugs which alter electrical excitability. Sodium and calcium channels are multi-subunit proteins with homologous principal subunits (designated alpha and alpha 1, respectively) that are associated with multiple auxiliary subunits. The principal subunits are about 2000 amino acids in length and contain four homologous domains having six transmembrane segments in each. Recent experiments probing the structure and function of sodium channels have led to new insight into the molecular basis of inactivation, one of the two voltage-dependent gating processes that control channel function, and have defined the primary structures and functional roles of the auxiliary beta 1 and beta 2 subunits of brain sodium channels. The extracellular domain of the beta 2 subunit has striking homology to neural cell adhesion molecules suggesting that its interaction with extracellular proteins may serve to localize or immobilize sodium channels.
Regulation of ion channel properties by physiological stimuli is of great interest as a potential mechanism of modulation of muscle contraction, hormone secretion, and information processing, learning, and memory in the central nervous system. Recently, we have made several advances in understanding the mechanism of regulation of sodium and calcium channels by protein phosphorylation and by interaction with G proteins. Sites of phosphorylation have been identified and related to specific functional effects on brain sodium channels, and G protein beta-gamma subunits have been shown to be responsible for modulation of presynaptic calcium channels. Future experiments will probe the molecular mechanisms of these regulatory effects and the functional interactions between the ion channel regulation by G proteins and protein phosphorylation.
Presynaptic calcium channels are responsible for the calcium entry that initiates exocytosis of neurotransmitters and fast synaptic transmission at synapses within 200 msec. Recent work in our laboratory has defined a synaptic protein interaction (synprint) site on these calcium channels which binds to the vesicle docking proteins syntaxin and SNAP-25. Peptides which block this interaction prevent fast and efficient transmitter release, and we hypothesize this protein-protein interaction serves to bring the docked synaptic vesicle close enough to presynaptic calcium channels to allow fast and efficient transmitter release. Future experiments will examine the regulation of this docking process and its possible role in synaptic plasticity.