Dr. Yoav Paas, a returning scientist from the Pasteur Institute, Paris, is a member of the Nano Medicine Center at the Institute of Nanotechnology and Advanced Materials (BINA) and a Senior Lecturer at the Mina and Everard Goodman Faculty of Life Sciences.
Paas is studying ligand-gated ion channels and, in collaboration with Prof. Uri Nir, controlled release of drugs from nanoparticles for the purpose of local discharge of chemotherapeutic drugs specifically at the site of tumor growth.
Pentameric ligand-gated ion channels (pLGICs) are Cys-loop receptors that bind neurotransmitters such as acetylcholine (ACh), serotonin, glycine, γ-aminobutyric acid (GABA), histamine or glutamate, thereby causing transient opening of an intrinsic transmembrane ion channel.
Opening of the receptor’s channel allows ions to flow across the cell membrane down their electro-chemical gradients, resulting in membrane depolarization (in the case of Na+/K+/(Ca2+)-selective pLGICs) or membrane hyperpolarization (in the case of Cl–-selective pLGICs). As a result, these ion channels mediate and regulate rapid transmission of chemo-electric signals throughout the central and peripheral nervous systems.
Hence, pLGICs play a key role in our day-to-day functions, from body motions to cognitive processes. Impairment of pLGICs’ activity leads to neurological disorders such as epilepsy, exaggerated startle responses, and congenital myasthenic syndromes. Serotonin-activated pLGICs are involved in irritable bowel syndrome, and ACh-activated pLGICs in the brain are responsible for addiction to nicotine in cigarette smokers.
Paas and his team are focused on the molecular and biophysical properties of pLGICs, including mechanisms of channel gating, mechanisms of ionic permeation and ionic selectivity, and mechanisms underlying coupling of neurotransmitter binding to channel activity.
In an attempt to discover new strategies for rational drug design, Paas and his team are also examining pharmacological properties of pLGICs, which include mechanisms of ligand recognition and ligand-induced activation or inhibition. To this end the team is working on the identification of the binding site for ivermectin (IVM) in various pLGICs.
IVM is an antiparasitic drug widely used in veterinary medicine, mainly in cattle, to kill intestinal worms. IVM is also used to treat parasitic diseases in humans like Onchocerciasis (river blindness). The major target of IVM is a heteropentameric glutamate-gated chloride channel (GluClα/β receptor), which is unique to invertebrates and belongs to the pLGIC superfamily.
Nanomolar concentrations of IVM irreversibly activate the native GluClα/βR, thereby causing sustained hyperpolarization, suppression of nervous impulses, paralysis and death of the nematode. At micromolar concentrations, IVM activates mammalian GABA- and glycine-gated ion channels, and enhances the activity of the brain α7-ACh receptor.
Little is known about the IVM binding site(s), and Paas and his team believe that details on the site at which IVM acts could shed light on the allosteric mechanism by which this drug acts. Hence this research might further assist in the design of novel drugs that will better modulate the activity of pLGICs under pathophysiological conditions.
The research in Paas’s laboratory employs recombinant DNA technology, protein engineering, ligand-binding assays, electrophysiological recordings, protein purification, protein crystallization and computer-assisted structural modeling.