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.
| Chapman, Mark L; Blanke, Marie L; Krovetz, Howard S et al. (2006) Allosteric effects of external K+ ions mediated by the aspartate of the GYGD signature sequence in the Kv2.1 K+ channel. Pflugers Arch 451:776-92 |
| Grigston, Jeffrey C; VanDongen, Hendrika M A; McNamara 3rd, James O et al. (2005) Translation of an integral membrane protein in distal dendrites of hippocampal neurons. Eur J Neurosci 21:1457-68 |
| Chapman, Mark L; VanDongen, Antonius M J (2005) K channel subconductance levels result from heteromeric pore conformations. J Gen Physiol 126:87-103 |
| VanDongen, Antonius M J (2004) Idealization and simulation of single ion channel data. Methods Enzymol 383:229-44 |
| Kalbaugh, Trisha L; VanDongen, Hendrika M A; VanDongen, Antonius M J (2004) Ligand-binding residues integrate affinity and efficacy in the NMDA receptor. Mol Pharmacol 66:209-19 |
| VanDongen, Antonius M J (2004) K channel gating by an affinity-switching selectivity filter. Proc Natl Acad Sci U S A 101:3248-52 |
| McNamara 2nd, James O; Grigston, Jeffrey C; VanDongen, Hendrika M A et al. (2004) Rapid dendritic transport of TGN38, a putative cargo receptor. Brain Res Mol Brain Res 127:68-78 |
| Jones, Kevin S; VanDongen, Hendrika M A; VanDongen, Antonius M J (2002) The NMDA receptor M3 segment is a conserved transduction element coupling ligand binding to channel opening. J Neurosci 22:2044-53 |
| Chapman, M L; Krovetz, H S; VanDongen, A M (2001) GYGD pore motifs in neighbouring potassium channel subunits interact to determine ion selectivity. J Physiol 530:21-33 |
| Wood, M W; VanDongen, H M; VanDongen, A M (1999) A mutation in the glycine binding pocket of the N-methyl-D-aspartate receptor NR1 subunit alters agonist efficacy. Brain Res Mol Brain Res 73:189-92 |
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