Menu
MapConnectionsTopicsBulgariaThe Night (K-TRIO)Marie Skłodowska-CurieFor studentsFor teachersMethodologySurprise me
H2020Individual fellowship2016–2018

ICaRO · Ion Channels and Receptors Operation

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2016-06-13 → 2018-06-12
EU contribution
€173,076
Participants
1
Scheme
MSCA-IF-EF-ST

Lines connect the coordinator with its partners.

Results in brief

Ion Channels and Receptors Operation

The physiological importance of ion channels is underlined by their involvement in a wide range of pathologies spanning all major therapeutic areas. Approximately 13% of known drugs have their primary therapeutic action at ion channels, making them the second largest target class after G-protein coupled receptors. However, our understanding of ion channel operation is limited to inferences based on functional data and to static snapshots of their structures where they are available. Cyclic nucleotide-modulated channels and calcium-activated K+ channels play crucial roles in a myriad of physiological processes ranging from signal transduction to neuronal excitability. The binding of ligands to specialized intracellular domains modulates the opening/closing (gating) equilibrium of these channels. Both the high-resolution structures - in open and closed conformation - of these channels and the precise mechanism of ligand-mediated channel activation are unknown. The present proposal aims to understand the mechanism of ion channel modulation by ligands. To accomplish this goal we utilized prokaryotic homologues of these channels reconstituted in artificial membranes. High-speed atomic force microscopy (HS-AFM) allowed us to directly observe individual ion channel molecules in action at high spatiotemporal resolution and in physiological conditions. Differences between liganded and unliganded channel structures provided us insight into the mechanism of ligand gating. The obtained data were compared to single channel current recordings obtained under comparable conditions.

Data: CORDIS, © European Union

Project objective

Our understanding of ion channel operation is limited to inferences based on functional data and to static snapshots of their structures where they are available. Cyclic nucleotide-modulated channels and calcium-activated K+ channels play crucial roles in a myriad of physiological processes ranging from signal transduction to neuronal excitability. The binding of ligands to specialized intracellular domains modulates the opening/closing (gating) equilibrium of these channels. Both the high resolution structures - in open and closed conformation - of these channels and the precise mechanism of ligand-mediated channel activation are unknown. The present proposal aims to understand the mechanism of ion channel modulation by ligands. To accomplish this goal we will utilize prokaryotic homologues of these channels reconstituted in artificial membranes. High-speed atomic force microscopy (HS-AFM) will allow us to directly observe individual ion channel molecules in action at high spatiotemporal resolution and in physiological conditions. Through UV-laser pulses caged ligands (caged-Ca2+ or caged-cAMP) will be liberated during HS-AFM imaging and the conformational changes associated to ligand binding monitored in real time. Differences between liganded and unliganded channel structures will provide insight into the mechanism of ligand gating. The obtained data will be compared to single channel current recordings under comparable conditions.

Original text from CORDIS.

Participants

  • INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisCoordinatorFrance

Links

Data: CORDIS, © European Union