Ion channels are proteins present in the cell membrane of both animal and plant tissues but are particularly present in the nervous system and heart where they transmit electrical signals. Their main function is to identify, select and guide specific ions and to respond to electrical, chemical and mechanical signals to regulate a variety of processes in a cell.
Our scientists are interested in exploring the mechanism of these membrane proteins and their potential applications to solve societal problems.
Recently, our researchers have expanded their interest to ion channels involved in neurodegenerative diseases. We study the voltage-gated potassium channel Kv4.3 at the single-molecule level, to understand how it works, how its function is modulated by accessory proteins and how its mutants cause neuronal death.
Our scientists have core competencies in the areas of synthetic biology, biochemistry, biophysics, and electrophysiology.
Neurobiology of ion channels is concerned with understanding the role of ionchannels in the healthy nervous system and elucidating why and how mutated ion channels cause dysfunction. Ion channels are membrane proteins responsible for neuronal excitability, signaling, and ion homeostasis. They are involved in a wide spectrum of essential functions including breathing, hearing, and learning.
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Our goal is to take advantage of the rapidly accumulating genetic information on ion channel disorders of the nervous system, combining it with my expertise on single channel structure-function relations to understand and control the electrical communication between excitable cells.
Our bottom-up approach is to determine the single channel properties of the wild-type and mutant ion channels and their interactions with the accessory proteins in a well-controlled, artificial, cell-like experimental system. Then, translating the findings back to the cellular level in cultured neurons. Currently, we are working on voltage-gated potassium channel Kv4.3 and GluA1/GluA2/GluA3 AMPA receptor channels
In order to reduce the toxicity and increase the efficacy of drugs, there is a need for smart drug delivery systems. Lipid-based systems are one of the promising tools for this purpose. An ideal delivery system should be stable, long-circulating, accumulating at the target site and releasing its drug in a controlled manner.
In vivo drug delivery to a brain tumor and drug release in response to the acidity of the tumor (MRI image)
Even though there have been many developments to this end, the dilemma of having a stable vehicle during circulation but converting it into a leaky structure at the target site is still a major challenge. So far, most attempts have focused on destabilizing the vehicle structure in response to a particular stimulus at a target site, but with limited success. Our approach is to generate long-circulating lipid-based nanovehicles with a build-in remote-controlled ion channel. The ion channel functions both as a sensor to detect target-specific cues and as a nanovalve to release the drug. We showed that the system can detect the mildly acidic pH of the tumor microenvironment with 0.2 pH unit precision and release their intraluminal content into C6 glioma tumors selectively, in vivo.
We are investigating how ion channels sense mechanical force at the molecular level. Mechanosensitive (MS) ion channels, present in membranes, are the molecules that sense membrane tension in all species ranging from bacteria to man. In recent years many diseases related to the malfunctioning of MS channels were discovered such as cardiac arrhythmias, polycystic kidney disease, hypertension, glioma, glaucoma, atherosclerosis, and tumorigenesis. In spite of their importance, their working mechanism is still unknown.
Mechanosensitive channel of large conductance, MscL
The “simplest” forms of MS channels from bacteria have been the objects of the study of mechanosensation for the past decade. They sense changes in membrane tension invoked by osmotic stress and as a response, they undergo structural rearrangements and generate large transient pores in the membrane. Even when isolated from their native membrane environment and reconstituted into artificial membranes composed of synthetic lipids, they are still capable of mechanosensing and responding to the alteration in membrane tension.
The long-term objective of my research is to understand the molecular mechanism of mechanosensation by analyzing individual forces acting on the system, those of the membrane acting on the protein and those of the protein acting on the membrane.
Toward the realization of sensory devices, there have been significant efforts on the use of synthetic or biological nanopores in single-molecule sensing platforms. The most attractive features of such systems are the ease of detection as the passage of analytes through the pores generates detectable changes in ionic pore current; no requirement of labeling or surface attachment of the analytes, and least their cost.
Among the pores, gated ion channels stand out for their intrinsic high sensitivity. They are natural excitable nanopores with two states: “closed (off)”, and “open (on)”. They are embedded in lipid bilayer membranes.
In this project, we engineer new functionalities into ion channels and incorporate them into hybrid devices with the final goal of obtaining very sensitive and stable biosensory devices.