Much of our work here is aimed at understanding the molecular and structural underpinnings of the generation of cellular electricity. All such phenomena - from the nerve action potential, to sensory transduction, to control of processes as varied as muscle contraction, hormone secretion, or blood volume homeostasis - are ultimately mediated by a single class of membrane proteins: the ion channels. We seek to understand the molecular mechanisms by which ion channel proteins open and close to switch the flows of ions across cellular membranes, and by which the open pore is able to choose so exquisitely which ions are able to permeate. Cellular electrical behavior requires ion gradients across biological membranes, and these gradients must be established by energy-consuming "transporter" proteins, which move ions "uphill." Our group also studies the mechanisms of transporters.
The lab focuses on channels and transporters that are approachable by a combination of attacks in reduced, biochemically defined systems. We use a combination of electrophysiological analysis, single-channel recording, membrane biochemistry, and x-ray crystallography to attack these problems, and each student is expected to gain experience in all these methods. Current efforts are directed at CLC Cl–-transporting proteins as well as a newly discovered subclass of these that specifically handle the cytotoxic F– ion. Our new interest in F- exporting proteins has also led us to stumble upon a phylogenetically unrelated and very unusual class of F–-specific ion channel proteins.
A few years ago, we discovered, to our shock and awe, that a bacterial homologue of CLC channels is not itself an ion channel, but rather functions as an ion "pump," stoichiometrically exchanging Cl- on one side of the membrane for H+ on the other. Using a combination of electrophysiology, membrane reconstitution, and x-ray crystallography, we are endeavoring to understand how these transport proteins work and also to comprehend the wider mechanistic implications of this co-habitation within the same molecular family of such fundamentally different ion-transport mechanisms.
Last, N. B., L. Kolmakova-Partensky, T. Shane and C. Miller (2016). "Mechanistic signs of double-barreled structure in a fluoride ion channel." elife. 2016 Jul 23;5.
Miller, C. (2016). "Reductionism redux." eLife. 2016; 5: e16964.
Tsai MF, Phillips CB, Ranaghan M, Tsai CW, Wu Y, Willliams C, Miller C (2016). "Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex." elife. 2016 Apr 21;5. pii: e15545. doi: 10.7554/eLife.15545.
Last NB and Miller C (2015). "Functional monomerization of a ClC-type fluoride transporter." J. Mol. Biol 427:3607-3612. doi: 10.1016/j.jmb.2015.09.027.
Stockbridge RB, Kolmakova-Partensky L, Koide A, Koide S, Miller C, and Newstead S. (2015). "Crystal structures of a double-barreled fluoride ion channel." Nature. 2015 Sep 24;525(7570):548-51.
Turman DL, Nathanson JT, Stockbridge RB, Street TO, and Miller C. (2015). "Two-sided block of a dual-topology F– channel." Proc Natl. Acad. Sci. USA 112:5607-5701. doi:pnas.1505301112.
Stockbridge RB, Koide A, Miller C, and Koide S.(2014). "Proof of dual-topology architecture of Fluc F- channels by monobody blockers." Nature Commun. 5:1-5. doi:10.1038/ncomms6120.
Miller C. "In the beginning: A personal reminiscence on the origin and legacy of ClC-0, the 'Torpedo Cl- channel'." J Physiol. 2014 pp. 1–6. doi: 10.1113/jphysiol.2014.286260.
Brammer A, Stockbridge RB, and Miller C. (2014). "F-/Cl- selectivity in CLCF-type F-/H+ antiporters." J. Gen Physiol. 144:129-136. doi 10.1085/jgp.201411225
Ji C, Stockbridge RB, and Miller C. (2014). "Bacterial fluoride resistance, Fluc channels, and the weak acid accumulation effect." J. Gen. Physiol.144:257-261. doi: 10.1085/jgp.201411243.
Tsai M-F, Jiang D, Zhao L, Clapham DE, and Miller C. (2014). "Functional reconstitution of the mitochondrial Ca2+-H+ antiporter Letm1." J. Gen. Physiol. 143:67-73. doi10.1085/jgp201311096.
Stockbridge RB, Robertson JL, Kolmakova-Partensky L, and Miller C. (2013). "A family of fluoride- specific ion channels with dual-topology architecture." eLife 2013:2:e01084.
Lim H-H, Stockbridge RB, and Miller C. (2013). "Fluoride-dependent interruption of the transport cycle of a CLC Cl-/H+ exchanger." Nature Chem. Biol. 9:721-725.
Tsai M-F and Miller C. (2013). "Substrate selectivity in arginine-dependent acid resistance in enteric bacteria." Proc Natl. Acad. Sci. USA 110:5893-5897.
Tsai M-F, McCarthy P, and Miller C. (2013). "Substrate selectivity in glutamate-dependent acid resistance in enteric bacteria." Proc Natl. Acad. Sci. USA 110:5898-5902.
Lim HH, Shane T, and Miller C. (2012). Intracellular proton access in a Cl-/H+ antiporter. PLoS Biol.10:1-8.
Stockbridge R, Lim HH, Otten R, Williams C, Shane T, Weinberg Z, and Miller C. (2012). Fluoride resistance and transport by riboswitch-controlled CLC antiporters.Proc. Natl. Acad. Sci. USA 109:15289-15294.
Tsai M-F, Fang Y, and Miller C. (2012). Sided functions of an arginine-agmatine exchange-transporter oriented in lipsomes. Biochemistry 51:1577-1585.
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Last reviewed: March 30, 2017.