Background

1. Leak potassium channels. Leak potassium currents exert control over cell excitability by shaping the duration, frequency and amplitude of action potentials, in part through their influence over the resting membrane potential. Increased potassium leak currents stabilize cells at hyperpolarized voltages, below the firing threshold of nerves and muscles, whereas leak suppression permits depolarization and excitation. To date, 15 human (KCNK genes, K2P proteins) and numerous fly, nematode and plant dedicated leak channels have been reported. Members of this channel family were found to play major roles in cell volume regulation, cell excitability, tumor development and survival, apoptosis, neuroprotection, heart function, anesthesia, polymodal pain perception, mental depression and oxygen sensing. Unique among potassium channels, K2P channels function as dimers. Each subunit has four transmembrane domains and, as their name implies, two pore-forming (P) domains.

2. Scorpion toxins. Scorpions are one of the most ancient group of animals on earth (more than 300 million years of evolution), represented today by approximately 1500 different species that are divided into four groups. The venoms of scorpions from the most studied group, the Buthida, are a rich source of small peptides, 23-78 amino acids-long, tightly-packed by the presence of either three or four disulfide bridges that affect ion channel function in excitable and non-excitable cells. These high-affinity modifiers are invaluable tools in the study of ion channels. Selective peptide ligands are fundamental to the understanding of channel localization, pore structure, subunit composition, tissue distribution and physiological roles. Due to their high selectivity, several toxin-based peptides are now being tested as potential remedies for maladies like brain tumors (chlorotoxin; TransMolecular Inc.).

Current Projects

1. Locating the gates of K2P channels and identification of possible coordination between gate activities- Voltage-gated potassium channels possess two functional gates, one being voltage sensitive (activation gate) and located at the internal side of the pore (bundle crossing), while the other resides at the external side of the pore (C-type inactivation gate). We had previously demonstrated the existence of the C-type like gate in a member of the K2P channel family, KCNK0. We now look for the presence of an internal gate.

2. Understanding the mechanism and pathway by which modulation of the two carboxy-terminal regulatory domains of a functional K2P channel leads to gating- The activities of the intracellular carboxy-terminl domains of the channels are controlled in response to intracellular signals, such as phosphorylation. We are looking for the molecular trail of the signal from the cytoplasm to the gates.

3. Revealing the significance of the extended first turret for K2P channels gating and conductance- The extracellular loop following the first transmembrane domain (turret) in K2P channels is exceptionally long. We study its relevance to channel gating and conductance.

4. Regulating K2P channels- K2P channels activity is highly regulated by both extra- and intra-cellular signals. We study the mode of action of several native channel modulators.

5. Scorpion venom evolution- The current arsenal of scorpion toxins is the outcome of an on-going battle between the scorpion and it's pray. We look at toxin variety to learn about the evolutionary mechanisms that enabled scorpion survival.

6. Isolation and characterization of novel scorpion toxins- We focus our attention on the isolation of toxins with selective activity towards insect potassium channels as well as toxins affecting potassium channels with no known blockers.

Recent Publications

Segal-Hayoun, Y., Cohen, A. and Zilberberg, N. (2010) Molecular mechanisms underlying membrane-potential-mediated regulation of neuronal K2P2.1 channels. Mol Cell Neurosci. 43:117-126.

Kozminsky-Atias, A. and Zilberberg, N. (2012) Molding the business end of neurotoxins by diversifying evolution. FASEB J. 26:576-586.

Drabkin, M., Zilberberg, N., Menahem, S., Mulla, W., Halperin, D., Yogev, Y., Wormser, O., Perez, Y., Kadir, R., Etzion, Y., Katz, A. and Birk, O.S. (2018) Nocturnal atrial fibrillation caused by a KCND2 mutation affecting the circadian rhythm-controlled cardiac Kv4.2 potassium channel. Circ: Genom. Precis. Med. 11:e002293.

Arazi, E, Blecher, G. and Zilberberg, N. (2020) A regulatory domain in the K2P2.1 (TREK-1) carboxyl-terminal allows for channel activation by monoterpenes. Mol Cell Neurosci. 105:103496.

Arazi, E, Blecher, G. and Zilberberg, N. (2020) Monoterpenes Differently Regulate Acid-Sensitive and Mechano-Gated K2P Channels. Front. Pharmacol. 11:704.

Ph.D. Tel Aviv University, 1997