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Structural dynamics and cellular distribution of ligand-gated ion channels: single molecule studies

English title Structural dynamics and cellular distribution of ligand-gated ion channels: single molecule studies
Applicant Vogel Horst
Number 118148
Funding scheme Project funding (Div. I-III)
Research institution Laboratoire de Chimie Physique des Polymères et Membranes EPFL - SB - ISIC - LCPPM
Institution of higher education EPF Lausanne - EPFL
Main discipline Biophysics
Start/End 01.01.2008 - 31.12.2010
Approved amount 425'000.00
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All Disciplines (3)

Discipline
Biophysics
Cellular Biology, Cytology
Biochemistry

Keywords (7)

Structural dynamics of ion channels; trafficking of neuroreceptors; synapse formation; electrophysiology; fluorescence spectroscopy & imaging; single molecule characterisation

Lay Summary (English)

Lead
Lay summary
Rapid synaptic signal transduction from one neuron to another or to non-neuronal cells like muscle cells is mediated by ligand-gated ion channels (LGICs). Neurotransmitters released by the axon of the presynaptic cell diffuse within millisecond across the synaptic cleft and bind to LGICs in the postsynaptic membrane resulting to a virtually immediate opening of the intrinsic ion channels of the activated LGICs. Activation of the postsynaptic cell is effected through cation-selective LGICs, the ionotropic receptors for glutamate, serotonin (5HT) and acetylcholine (ACh). The latter receptor type is responsible for the initiation of muscle contraction in vertebrates. Neurotransmitter release is regulated in part by presynaptic LGICs that are activated by signalling molecules diffusing out of the synaptic cleft. The ionotropic receptor for serotonin is often found on the peri-synaptic part of axons.The importance of LGICs for functioning of and communication between cells within humans and their implication in many hereditary or acquired diseases has motivated many research efforts, resulting in the fact that this class of membrane receptors is a major target of presently used medicines. Nevertheless, central questions about the molecular architecture and structural dynamics, and the synaptic organisation and function of LGICs remain to be solved.Here, we plan to continue to investigate two representative LGICs, the muscle-type nicotinic acetylcholine receptor (nAChR) and the serotonin type-3 receptor (5HT3R), and will focus on the following:How does a cell traffick LGICs and how does this affect cellular signalling?Presence and activity of LGICs on the cell surface is highly regulated. In-vivo fluorescence labelling and imaging will be used to study the formation of the neuromuscular junction (NMJ), especially the interplay between nAChR and the scaffold proteins in the clustering and trafficking of the receptor to the NMJ. We will study diffusion and lateral distribution of single receptor molecules with respect to scaffold proteins. The effect of myasthenia related mutations in these proteins on NMJ formation and maintenance will be characterized. How does ligand binding induce the gating of the ion channel? The central question how binding of an agonist to the extra-cellular ligand binding domain of a LGIC induces the cascade of structural changes needed to open the distant trans-membrane channel, is unresolved. Simultaneous measurement of the binding of fluorescent agonists to a single receptor and single channel conductance will probe how the sequential binding of several agonist molecules to one receptor protein is linked to channel gating. This will allow for the first time to fully describe the mechanism of ligand-induced channel gating.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
133141 Structure and function of ionotropic serotonin and acetylcholine receptors 01.01.2011 Project funding (Div. I-III)
109886 Structural dynamics and cellular distribution of ligand-gated ion channels: Single molecule studies 01.10.2005 Project funding (Div. I-III)

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