Ion channels are the primary sensors of many physical stimuli such as voltage, lateral stretch, osmolality and temperature. Of these, the fundamental biophysical principles of temperature-sensing and temperature- dependent gating are perhaps the most enigmatic. Despite the fact that many ion channels in the voltage- gated ion channel (VGIC) superfamily are involved in temperature sensing and that many high-resolution structures are now available, a common structural motif or module responsible for this temperature- dependence has not yet been identified. One possibility is that temperature-sensing phenotype is due to convergent evolution and different ion channels have become temperature-sensitive in different ways. According to this line of thinking, unlike a chemical signal, temperature gating may have less to do with a specific structural fold since it is not bound by rules of stereochemistry. The goal of this proposal is to broadly explore the mechanisms of temperature-dependent gating in ion channels using a multi-pronged approach.
In specific aim 1, we will apply the newly developed thermodynamic tools and multi-dimensional NMR spectroscopy to thoroughly characterize the biophysical mechanisms that underlie enhanced temperature- sensitive gating in engineered ion channels. We will test the hypothesis that state-dependent change in solvation of side-chains and lipid acyl chains may underlie temperature-dependence in these ion channels. In the specific aim 2, we will explore the temperature-dependence of electromechanical coupling. The goal here is to use rational design approach to test an alternate mechanism of temperature sensing. In this paradigm, the temperature-sensitivity is not due to the sensor itself but due to temperature-dependence of coupling interactions between the voltage-sensor and pore gates.
In specific aim 3, we will probe the mechanisms of temperature-dependent gating in a biochemically tractable prokaryotic channel. We have recently identified that the calcium-dependent gating of MthK potassium ion channel is highly temperature-sensitive. Our proposed studies will combine calorimetry, electrophysiology and structural biology with the power of reverse genetics to understand the molecular mechanisms that underlie temperature-dependence in these archeal ion channels. Taken together, the three specific aims will broadly study the mechanisms of temperature-dependent gating in channels of the VGIC superfamily. We expect that this multi-disciplinary approach will shed light on the biophysical mechanisms that underlie exquisite temperature-dependence in many ion channels.
The ability to sense and respond to temperature is critical for evolutionary success and, consequently, biological organisms have evolved a variety of mechanisms for sensing temperature. Many of the primary sensors of thermal stimuli are membrane proteins that belong to the voltage-gated ion channel superfamily. This project addresses fundamental questions regarding the mechanisms that determine temperature- sensitivity in these ion channels and also focuses on developing new models to study this phenomenon. Insights gained from this study may help develop advance treatments to cure diseases such as neuropathic pain and multiple sclerosis.
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| Fernández-Mariño, Ana I; Harpole, Tyler J; Oelstrom, Kevin et al. (2018) Gating interaction maps reveal a noncanonical electromechanical coupling mode in the Shaker K+ channel. Nat Struct Mol Biol 25:320-326 |
| Goldschen-Ohm, Marcel P; Chanda, Baron (2017) SnapShot: Channel Gating Mechanisms. Cell 170:594-594.e1 |
| Goldschen-Ohm, Marcel P; White, David S; Klenchin, Vadim A et al. (2017) Observing Single-Molecule Dynamics at Millimolar Concentrations. Angew Chem Int Ed Engl 56:2399-2402 |
| Zhao, Yaxian; Goldschen-Ohm, Marcel P; Morais-Cabral, João H et al. (2017) The intrinsically liganded cyclic nucleotide-binding homology domain promotes KCNH channel activation. J Gen Physiol 149:249-260 |
| Goldschen-Ohm, Marcel P; Klenchin, Vadim A; White, David S et al. (2016) Structure and dynamics underlying elementary ligand binding events in human pacemaking channels. Elife 5: |
| Ahern, Christopher A; Payandeh, Jian; Bosmans, Frank et al. (2016) The hitchhiker's guide to the voltage-gated sodium channel galaxy. J Gen Physiol 147:1-24 |
| Bao, Huan; Goldschen-Ohm, Marcel; Jeggle, Pia et al. (2016) Exocytotic fusion pores are composed of both lipids and proteins. Nat Struct Mol Biol 23:67-73 |
| Goldschen-Ohm, Marcel P; Chanda, Baron (2015) How to open a proton pore-more than S4? Nat Struct Mol Biol 22:277-8 |
| Chowdhury, Sandipan; Haehnel, Benjamin M; Chanda, Baron (2014) Interfacial gating triad is crucial for electromechanical transduction in voltage-activated potassium channels. J Gen Physiol 144:457-67 |
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