Affiliations

Professor, Anesthesiology, Physiology

Member, Molecular Medicine, Biochemistry, Biophysics & Structural Biology GPB Home Area, Brain Research Institute, Molecular, Cellular & Integrative Physiology GPB Home Area, Neuroscience GPB Home Area

Faculty, Cardiovascular Research Laboratory

The general aim of my research is to define the role of ion channels in the control and regulation of cell excitability. Ion channels are membrane proteins that regulate the flow of ions across the cell membrane that in turn control a variety of functions such as neuronal excitability, heartbeat, muscle contraction and hormones release. Ion channels are transmembrane proteins usually associated with accessory subunits that modulate their function. The regulation mechanism(s) of voltage dependent channel activity by accessory subunits and second messengers is one of my strongest interests. In these studies, by combining state-of-the-art electrophysiological techniques (cut-open oocyte voltage clamp, patch clamp, macropatch) with mutagenesis, we identifying the structural determinants for the various channel functions (activation, inactivation, conduction and sensitivity to drugs). STRUCTUTRAL REARRANGEMENTS OF CHANNEL PROTEINS DURING GATING Voltage-dependent ion channels respond to changes of membrane potential by a rearrangement of a voltage sensing structure. The movement of the voltage sensor produces a conformational change of the channel that allows ion conduction through the pore. Part of my research is currently dedicated to understand the coupling mechanism between the movements of the voltage sensor and pore opening. This study involves the measurement of small currents (gating currents) generated by the movement of the charged voltage sensor across the transmembrane electric field. Gating currents reveal the conformational changes of the channel protein, occurring before and during channel opening. In this research program, we combine optical methods with classical electrophysiology to detect conformational changes of the channels. This novel approach in ion channels studies allows detecting conformational changes of channel protein as changes in fluorescence properties of fluorophores covalently attached to selected positions on the protein (voltage clamp + site directed fluorescence labeling). One of the goals is to correlate at the molecular level the structural changes of the channel protein with the different phases of channel activity. At this moment, I am using this approach to investigate the properties of voltage and calcium activated (BK) channels. The final objective is to obtain a molecular and dynamic view of BK channels by identifying the mobile regions underlying voltage sensing. MECHANISMS OF ION PERMEATION THROUGH ION CHANNEL: We are currently investigating how the amino acids in close proximity of the conduction pore are affecting the conduction properties of voltage- and calcium-activated K+ channels. In combination with theoretical, biophysical and pharmacological studies, we learn about the basic mechanism of ion permeation and channel gating at the molecular level. One of the objectives is to understand the unique permeation properties of BK channels, which allow K+ to permeate 20fold better in respect to other potassium channels that share very similar amino acid pore sequences. CARDIAC ARRHYTHMIAS AND FIBRILLATION In collaboration with Dr J. Weiss, we are developing a research program focused cardiac arrhythmias and fibrillation. Activation and inactivation of voltage dependent calcium channels play a key role in the stability of the cardiac rhythm, through their effects on action potential properties. The goal is to is to control cardiac excitability, by fine tuning the the activity of cardiac L-type calcium channels using their own modulatory subunits. The project should set basis for a larger gene-therapy related project

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