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In Focus - Avi Priel
Avi Priel was born and raised in Omer. After the completion of his military service, Avi began his undergraduate studies in the Department of Chemistry in Ben-Gurion University, during which he became fascinated by biological and pharmacological systems. Throughout his graduate studies, Avi investigated the regulatory mechanisms that regulate the activation of ligand-gated ion channels. 

During the MSc portion of his graduate studies, he worked under the supervision of Prof. Shai D. Silberberg at Ben-Gurion University and studied P2X purinoreceptors, which are ligand-gated ion channels that are activated by extracellular ATP. His analyzed the biophysical and pharmacological mechanisms of ivermectin (IVM) modulation of the human P2X4 receptor.  Ivermectin is a semi-synthetic derivative of the natural fermentation products of Streptomyces avermitilis, and is widely used in human and veterinary medicine as an anti-parasitic agent.  In humans, more than 18 million people receive IVM annually, predominantly to treat onchocerciasis (also known as river blindness).  His findings showed that IVM modulates the current, amplitude, and rate of deactivation of P2X4, what results in increased sensitivity to ATP in expressing cells (published in The Journal of General Physiology).

diagram of cold and heat noxious

For his PhD studies, he moved to Jerusalem on 2003. During his PhD work under the supervision of Prof. Yael Stern-Bach at the Hebrew University, he investigated mechanisms that regulate the gating of ionotropic glutamate receptors (iGluRs).  Specifically, he studied members of the AMPA and kainate subfamilies, which are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. Two main projects were conducted during this period. The aim of the first project was to characterize the role of an auxiliary protein, Stargazin, in modulating AMPA receptor function. Stargazin was shown to play a major role in the trafficking of AMPA receptors to both the plasma membrane and to synapses.  Avi discovered that Stargazin also plays a significant role in AMPA receptor gating and activation.  These results offered a solution for a long-standing question regards the distinct outcome of receptor activation in neurons and heterologous system (published in The Journal of Neuroscience). The second project explored the mechanism of kainate receptor activation and desensitization. Both AMPA and kainate receptors desensitize rapidly and completely in response to glutamate, with a time constant of < 5 ms. This profound desensitization, together with a slow recovery, is thought to play an important role in determining the frequency and amplitude of excitatory responses in the brain. Avi established that stabilization of the interface between adjacent ligand-binding domains, through the generation of intermolecular disulfide bonds, blocks desensitization of the kainate receptor GluR6.  Moreover, the mechanism he uncovered established a common desensitization mechanism for both AMPA and kainate receptors. He showed that the surface expression of non-desensitizing mutants was drastically reduced and completely unaffected by channel activity.  This indicates that desensitization is not only important for synaptic functions, but also has a crucial intracellular role, controlling the maturation and trafficking of glutamate receptors (published in Neuron). In 2008, Avi received his PhD from the Hebrew University, Summa cum laude.

diagram of bivalent and high avidity activating interaction

For his postdoctoral studies, Avi joined the laboratory of Prof. David Julius at the University of California, San Francisco (UCSF), where he studied the somatosensory receptors of the TRP family.  These receptors have an essential role in the detection of temperature and chemical stimuli throughout the body.  Additionally, the somatosensory system plays a protective role by detecting noxious and inflammatory stimuli. The Julius group has pioneered the use of expression cloning to identify key signaling molecules in the somatosensory system and, through seminal contributions over the past two decades, has become a leading lab in the field of somatosensation. During his postdoc, Avi identified a new peptide toxin from the aggressive Chinese earth tiger spider (Ornithoctonus huwenum).  This toxin specifically activates the capsaicin or ‘heat’ receptor (TRPV1) in both native (trigeminal sensory neurons) and heterologous (HEK293 and Xenopus laevis oocytes) systems.  This novel peptide has unusual structure: two toxin motifs are joined together as a bivalent ligand, which led to its name the ‘double knot toxin’ (DkTx).  He found that this toxin binds to TRPV1 in an irreversible manner, resulting in persistent activation of the receptor with the presumed behavioral outcome of prolonged pain and pronounced neurogenic inflammation. He delineated the molecular mechanism of this interaction on both the receptor and the toxin using a variety of techniques.  He showed that the toxin contains two independently folded inhibitory cysteine knot (ICK) domains, which provide it with an antibody-like bivalency resulting in extremely high avidity for its multimeric channel target.  This characteristic makes it a powerful biochemical tool for probing TRP channel function (published in Cell).

Dr. Avi Priel has been a faculty member in the Institute for Drug Research (IDR) at the School of Pharmacy (the Pharmacology section) since September 2011. His group studies the molecular and cellular aspects of pain receptors. These receptors are found only in the pain system and may serve as an excellent target for drugs which will be specific to the pain system with minimal side effect. These stands in contrast to the pain medication being used to date, which have severe side effects to the point of diminish return. His group relies on different techniques including: molecular biology, biochemistry of proteins and peptides, electrophysiology and live-cell imaging. They study somatosensory neurons, mainly nociceptors, and uses culture cells like HEK293, CHO-K1 and so on.

Somatosensation is complex and multi-faceted system that presents numerous scientific challenges.  For example, this system is responsible for full range of thermosensation (cold, warm, heat, and painful heat), chemical irritants, mechanosensation (from a light breeze to a painful punch) and so on.  Besides sensing the environment, the somatosensory system is also involved in internal sensation.  All visceral organs are innervated by this system, which can be engaged during various disease processes.  The approach the Priel lab is taking is to understand how these events take place on both the neuronal and molecular levels.  In addition, the lab is exploring and developing novel and specific pharmacological tools to isolate the different mechanisms of this system.​

Avi Priel
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