STRUCTURAL BASIS OF ION CHANNEL OPENING

Duke University, Durham NC

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Abstract

DESCRIPTION The long term objective of this project is to elucidate the molecular basis of ion channel behavior. A universal property of ion channels is that they open and close stochastically. Both ligand- and voltage-gated channels share a common architecture of subunits or domains arranged around a central pore. The pore-forming regions of K channels and glutamate receptors seem to be structurally conserved, suggesting that fundamental channel functions like permeation and gating may share a molecular basis. Open/close transitions usually involve a coordinated movement of all subunits contributing to the pore. However, this concerted behavior seems to break down in partially activated K channels, giving rise to subconductance levels. In this project the role of individual subunits in shaping channel behavior will be further evaluated using the drk1 K channel and the NMDA receptor as model systems. Specific aims are: (i) To determine the role of individual subunits in permeation and gating; (ii) To determine how ion selectivity is affected by subunit composition; (iii) To determine subunit-subunit interactions in channel activation. For each model system, mutations are available in which activation, permeation, or selectivity are severely compromised. Significance: understanding channel behavior at the molecular level will help establish a molecular basis for disorders in which excitability and neurotransmission are impaired. The ability to explain fundamental aspects of ion channel function in terms of molecular structure is also a prerequisite for rational drug design.