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.

The laboratory focuses on a broad class of ion channels - the CLC-type Cl- channels. These proteins are interesting because so little is known about them, despite the fact that high-resolution x-ray crystal structures are now known for some. The relationship between structure and functional behavior is an area of active investigation here, using bacterial CLC homologues and a combination of x-ray crystallography and electrophysiological analysis.

We recently discovered, to our shock and awe, that a bacterial homologue of this Cl- channel family 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 ransport 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.

Selected Publications

Structure of a prokaryotic virtual proton pump at 3.2 Å resolution. Fang, Y., Jayaram, H., Shane, T., Kolmakova-Partensky, L., Wu, F., Williams, C., Xiong, Y., and Miller, C.  2009 Nature 460:1040-1043. [abstract]

Intracellular proton-transfer mutants in a bacterial CLC Cl-/H+ exchanger. Lim, H.H. and Miller, C. 2009. J. Gen. Physiol. 133:131-138. [abstract]

A provisional mechanism for Cl-/H+ exchange in CLC transport proteins. Miller, C. and Nguitragool, W. 2009. Phil. Trans. Roy. Soc. B. 364:175-180. [abstract]

Ion permeation through a Cl--selective channel designed from a CLC Cl-/H+ exchanger. Jayaram, H., Accardi, A., Wu, F., Williams, C., and Miller, C. 2008. Proc. Natl. Acad. Sci. USA 105: 11194-11199. [abstract]

CLC Cl-/H+ exchangers constrained by covalent cross-linking. Nguitragool, W. and Miller, C. 2007. Proc. Natl. Acad. Sci. USA 104:20659-20665. [abstract]

Uncoupling and turnover in a CLC Cl-/H+ exchanger. Walden, M., Accardi, A.,Wu, F., Xu,C., Williams, C., and Miller, C. 2007. J. Gen. Physiol. 129:317-329. [abstract]

A bacterial arginine-agmatine exchange transporter involved in extreme acid resistance. Fang, Y., Kolmakova-Partensky, L., and Miller, C. 2007. J. Biol. Chem. 282:176-182. [abstract]

Synergism between halide binding and proton transport CLC-type exchanger. Accardi, A., Lobet, S., Williams, C., Miller, C., and Dutzler, R. 2006. J. Mol. Biol. 362:691-699. [abstract]

Uncoupling of a CLC Cl-/H+ exchange transporter by polyatomic anions. Nguitragool, W. and Miller, C. 2006. J. Mol. Bio. 362:682-690. [abstract]

CLC chloride channels viewed through a transporter lens. Miller, C. 2006. Nature 440:484-489.

Small vertical movement of a K+ channel voltage sensor measured with luminescence energy transfer. Posson, D.J., Ge, P. Miller, C. Bezanilla, F., and Selvin, P.R. 2005. Nature 436:848-851. [abstract]

A cyclic nucleotide modulated prokaryotic K+ channel. Nimigean, C.M., Shane, T., and Miller, C. 2004. J Gen Physiol. 124:203-210. [abstract]

Secondary active transport mediated by a prokaryotic homologue of CLC Cl- channels. Accardi, A. and Miller, C. 2004. Nature 427:803-807. [abstract]

View Complete Publication List on PubMed: Chris Miller

---

Last reviewed: September 1, 2009.