Prof. Ilana Lotan

Professor, Department of Physiology & Pharmacology, Sackler Faculty of Medicine

Role of Potassium Channels in Neurotransmitter and Insulin Release in Diabetes

We have a long-standing interest in the study the molecular mechanisms of modulation of voltage gated K⁺ (Kv) channels by interaction with signaling molecules. We were first to describe modulation of a brain Kv channel by major protein components of the exocytotic machinery. Since then our main focus is the role of Kv channels in transmitter release, finding that it may be far more than just repolarizing the membrane potential: independent of K⁺ currents but mediated by protein-protein interactions with the exocytic SNARE proteins. The dual actions of the channel, through its currents and via its interaction with SNAREs, in combination, may reinforce the known activity dependence of dense core vesicle exocytosis.

Main research projects currently in the lab:

1. Study of the novel role of Kv2.1 potassium channel in insulin secretion from pancreatic islet β cells, as a target for novel drug design for the treatment of type-2 diabetes;
2. Study of structure-function and modulations by presynaptic modulators of Kv2.1 and other Kv channels, specifically KCNQ2 and KCNQ3, important in axonal and synaptic excitability.

Research methods:

• Biophysical: 1) Two-electrode voltage clamp and patch clamp techniques for the study of whole cell and single channel currents. 2) Membrane capacitance and amperometry measurements for the study of exocytosis.
• Biochemical: co-immunoprecipitation, immunohystochemistry, recombinant protein purification, etc, for the study of in vivo and in vitro protein-protein interactions.
• Imaging: 1) Fluorescence Resonance Energy Transfer (FRET) for the study of protein-protein interactions. 2) Total Internal Reflection Fluorescence Microscopy (TIRFM) for the study of neurotransmitter vesicles behavior.

Feinshreiber, L., Singer-Lahat, D., Friedrich, R., Matti, U, Sheinin, A., Yizhar, O., Nachman, R., Chikvashvili, D., Rettig, J., Ashery, U. and Lotan, I. Non-conducting function of the Kv2.1 channel enables it to recruit vesicles for release in neuroendocrine and nerve cells. J Cell Sci. 123:1940-7 (2010)

Etzioni, A., Siloni, S., Chikvashvilli, D., Strulovich, R., Sachyani, D., Regev, N., Greitzer-Antes, D., Hirsch, J.A.  and Lotan, I. Regulation of neuronal M channel gating in an isoform–specific manner; functional interplay between calmodulin and syntaxin 1A. J Neurosci. 31:14158-71 (2011).

Dai XQ, Manning Fox JE, Chikvashvili D, Casimir M, Plummer G, Hajmrle C, Spigelman AF, Kin T, Singer-Lahat D, Kang Y, Shapiro AM, Gaisano HY, Lotan I, Macdonald PE. The voltage-dependent potassium channel subunit Kv2.1 regulates insulin secretion from rodent and human islets independently of its electrical function. Diabetologia. 2012;55:1709-20.

Lotan I, Khlebtovsky A, Inbar E, Strenov J, Djaldetti R, Steiner I. Primary brain T-cell lymphoma in an HTLV-1 serologically positive male. J Neurol Sci. 2012;314:163-5.

Greitzer-Antes D, Barak-Broner N, Berlin S, Oron Y, Chikvashvili D, Lotan I. Tracking Ca2+-dependent and Ca2+-independent conformational transitions in syntaxin 1A during exocytosis in neuroendocrine cells. J Cell Sci. 2013;126:2914-23.

Hellmann MA, Mosberg-Galili R, Lotan I, Steiner I. Maintenance IVIg therapy in myasthenia gravis does not affect disease activity. J Neurol Sci. 2014;338:39-42.

Reviews

Michaelevski, I. and Lotan, I. Role of neuronal potassium M-channels in sympathetic regulation of cardiac function. J Physiol. 589:2659-2660 (2011).

McCord MC, Kullmann PH, He K, Hartnett KA, Horn JP, Lotan I, Aizenman E. Syntaxin-binding domain of Kv2.1 is essential for the expression of apoptotic K+ currents. J. Physiol. 2014;592:3511-21.

Vertkin I, Styr B, Slomowitz E, Ofir N, Shapira I, Berner D, Fedorova T, Laviv T, Barak-Broner N, Greitzer-Antes D, Gassmann M, Bettler B, Lotan I, Slutsky I. GABAB receptor deficiency causes failure of neuronal homeostasis in hippocampal networks. Proc. Natl Acad Sci USA. 2015;112:E3291-9.

Siloni S, Singer-Lahat D, Esa M, Tsemakhovich V, Chikvashvili D, Lotan I. Regulation of the neuronal KCNQ2 channel by Src – a dual rearrangement of the cytosolic termini underlies bidirectional regulation of gating. J Cell Sci. 2015;128, 3489-3501.

• 2014-2018 Israel Science Foundation