Home > Publications

Nature Communications

Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB

Published on 06.23.2018 in Nature Communications

Authors: Appu K. SinghKei Saotome, Luke L. McGoldrick, Alexander I. Sobolevsky

Transient receptor potential (TRP) channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its expression is dramatically increased in numerous types of cancer. TRPV6 inhibitors suppress tumor growth, but the molecular mechanism of inhibition remains unknown…


Taylor and Francis

X-ray crystallography of TRP channels

Published on 04.30.2018 in Channels

Authors: Appu K. Singh, Luke L. McGoldrick, Kei Saotome, Alexander I. Sobolevsky  

Transient receptor potential (TRP) ion channels are molecular sensors of a large variety of stimuli including temperature, mechanical stress, voltage, small molecules including capsaicin and menthol, and lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2). Since the same TRP channels may respond to different physical and chemical stimuli, they can serve as signal integrators…


Scientific Reports

Ion permeation mechanism in epithelial calcium channel TRVP6

Published on 04.09.2018 in Scientific Reports

Authors: Serzhan Sakipov, Alexander I. SobolevskyMaria G. Kurnikova

Calcium is the most abundant metal in the human body that plays vital roles as a cellular electrolyte as well as the smallest and most frequently used signaling molecule. Calcium uptake in epithelial tissues is mediated by tetrameric calcium-selective transient receptor potential (TRP) channels TRPV6 that are implicated in a variety of human diseases, including numerous forms of cancer…


British Pharmacological Society

Proton-independent activation of acid-sensing ion channel 3 by an alkaloid, lindoldhamine, from Laurus nobilis

Published on 12.26.2017 in British Journal of Pharmacology

Authors: Dmitry I. Osmakov, Sergey G. Koshelev, Yaroslav A. Andreev, Maxim A. Dubinnyi, Vadim S. Kublitski, Roman G. Efremov, Alexander I. Sobolevsky, Sergey A. Kozlov

Acid-sensing ion channels (ASICs) play an important role in synaptic plasticity and learning, as well as in nociception and mechanosensation. ASICs are involved in pain and in neurological and psychiatric diseases, but their therapeutic potential is limited by the lack of ligands activating them at physiological pH. We extracted, purified and determined the structure of a bisbenzylisoquinoline alkaloid, lindoldhamine, (LIN) from laurel leaves…


Nature

Opening of the human epithelial calcium channel TRPV6

Published on 12.20.2017 in Nature

Authors: Luke L. McGoldrick, Appu K. Singh, Kei Saotome, Maria V. Yelshanskaya, Edward C. Twomey, Robert A. GrassucciAlexander I. Sobolevsky

Calcium-selective transient receptor potential vanilloid subfamily member 6 (TRPV6) channels play a critical role in calcium uptake in epithelial tissues. Altered TRPV6 expression is associated with a variety of human diseases, including cancers. TRPV6 channels are constitutively active and their open probability depends on the lipidic composition of the membrane in which they reside…


Biochemistry

Structural mechanisms of gating in ionotropic glutamate receptors

Published on 10.16.2017 in Biochemistry

Authors: Edward C. TwomeyAlexander I. Sobolevsky

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in the central nervous system. iGluRs open their ion channels in response to binding of the neurotransmitter glutamate, rapidly depolarize the postsynaptic neuronal membrane, and initiate signal transduction…


Nature

Channel opening and gating mechanism in AMPA-subtype glutamate receptors

Published on 07.24.2017 in Nature

Authors: Edward C. Twomey, Maria V. Yelshanskaya, Robert A. Grassucci, Joachim FrankAlexander I. Sobolevsky

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission throughout the central nervous system. Gated by the neurotransmitter glutamate, AMPA receptors are critical for synaptic strength, and dysregulation of AMPA receptor-mediated signalling is linked to numerous neurological diseases…


Taylor and Francis

Determining the crystal structure of TRPV6

Published on 06.08.2017 in Calcium Entry Channels in Non-Excitable Cells

Authors: Appu K. Singh, Kei Saotome, Alexander I. Sobolevsky  

The concept of signal transduction is now long established as a central tenet of biological sciences. Since the inception of the field close to 50 years ago, the number and variety of signal transduction pathways, cascades, and networks have steadily increased and now constitute what is often regarded as a bewildering array of mechanisms by which cells sense and respond to extracellular and intracellular environmental stimuli…


Neuron

Structural bases of desensitization in AMPA receptor-auxiliary subunit complexes

Published on 05.03.2017 in Neuron

Authors: Edward C. Twomey, Maria V. Yelshanskaya, Robert A. Grassucci, Joachim FrankAlexander I. Sobolevsky

Fast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits that modulate AMPAR assembly, trafficking, gating, and pharmacology. Aberrancies in AMPAR-mediated signaling are associated with numerous neurological disorders…


Scientific Reports

Role of the ion channel extracellular collar in AMPA receptor gating

Published on 04.21.2017 in Scientific Reports

Authors: Maria V. Yelshanskaya, Samaneh Mesbahi-Vasey, Maria G. KurnikovaAlexander I. Sobolevsky

AMPA subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission and are implicated in numerous neurological diseases. Ionic currents through AMPA receptor channels can be allosterically regulated via different sites on the receptor protein. We used site-directed mutagenesis and patch-clamp recordings to probe the ion channel extracellular collar, the binding region for noncompetitive allosteric inhibitors…


Neuron

Structural bases of noncompetitive inhibition of AMPA-subtype ionotropic glutamate receptors by antiepileptic drugs

Published on 09.08.2016 in Neuron

Authors: Maria V. Yelshanskaya, Appu K. Singh, Jared M. Sampson, Chamali Narangoda, Maria Kurnikova, Alexander I. Sobolevsky

Excitatory neurotransmission plays a key role in epileptogenesis. Correspondingly, AMPA-subtype ionotropic glutamate receptors, which mediate the majority of excitatory neurotransmission and contribute to seizure generation and spread, have emerged as promising targets for epilepsy therapy. The most potent and well-tolerated AMPA receptor inhibitors act via a noncompetitive mechanism, but many of them produce adverse side effects…


Science

Elucidation of AMPA receptor-stargazin complexes by cryo-electron microscopy

Published on 07.01.2016 in Science

Authors: Edward C. Twomey, Maria V. Yelshanskaya, Robert A. Grassucci, Joachim Frank, Alexander I. Sobolevsky

AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and contribute to high cognitive processes such as learning and memory. In the brain, AMPAR trafficking, gating, and pharmacology is tightly controlled by transmembrane AMPAR regulatory proteins (TARPs)…


Nature

Crystal structure of the epithelial calcium channel TRPV6

Published on 06.13.2016 in Nature

Authors: Kei Saotome, Appu K. Singh, Maria V. Yelshanskaya, Alexander I. Sobolevsky

Precise regulation of calcium homeostasis is essential for many physiological functions. The Ca2+-selective transient receptor potential (TRP) channels TRPV5 and TRPV6 play vital roles in calcium homeostasis as Ca2+ uptake channels in epithelial tissues. Detailed structural bases for their assembly and Ca2+ permeation remain obscure…


Scientific Reports

Probing intersubunit interfaces in AMPA-subtype ionotropic glutamate receptors

Published on 01.07.2016 in Scientific Reports

Authors: Maria V. Yelshanskaya, Kei Saotome, Appu K. Singh, Alexander I. Sobolevsky

AMPA subtype ionotropic glutamate receptors (iGluRs) mediate the majority of fast neurotransmission across excitatory synapses in the central nervous system. Each AMPA receptor is composed of four multi-domain subunits that are organized into layers of two amino-terminal domain (ATD) dimers, two ligand-binding domain (LBD) dimers, transmembrane domains and carboxy-terminal domains…


Springer

Expression, purification, and crystallization of full length ionotropic glutamate receptors

Published on 01.07.2016 in Neuromethods

Authors: Maria V. Yelshanskaya, Kei Saotome, Minfen Li, Alexander I. Sobolevsky

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in brain and are implicated in nearly all aspects of central nervous system development and function. There is great clinical interest in iGluRs because their dysfunction is associated with chronic neurodegenerative conditions, psychiatric disorders, brain trauma and stroke…


Science

Structure of an agonist-bound ionotropic glutamate receptor

Published on 08.29.2014 in Science

Authors: Maria V. Yelshanskaya, Minfen Li, Alexander I. Sobolevsky

Ionotropic glutamate receptors (iGluRs) mediate most excitatory neurotransmission in the central nervous system and function by opening their ion channel in response to binding of agonist glutamate. Here, we report a structure of a homotetrameric rat GluA2 receptor in complex with partial agonist (S)-5-nitrowillardiine…


The Journal of Physiology

Structure and gating of tetrameric glutamate receptors

Published on 11.06.2013 in The Journal of Physiology

Authors: Alexander I. Sobolevsky

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that open their ion-conducting pores in response to the binding of agonist glutamate. In recent years, significant progress has been achieved in studies of iGluRs by determining numerous structures of isolated water-soluble ligand-binding and amino-terminal domains, as well as solving the first crystal structure of the full-length AMPA receptor in the closed, antagonist-bound state…


PubMed

Sobolevsky Lab publication list

Published on 1998-2018 in PubMed

Authors: Alexander I. Sobolevsky

Based in the Department of Biochemistry and Molecular Biophysics at Columbia University Medical Center, we study ion channel signaling using cryo-electron microscopy, X-ray crystallography, electrophysiology and biophysical techniques…