Tsung-Yu Chen, M.D., Ph.D.
Structures, Functions and Physiology of Ion Channels
The long term interest in my laboratory is to understand structures, functions, and physiological roles of a class of transmembrane proteins called ion channels. These proteins control ion fluxes across cell membranes, and in doing so maintain normal physiological functions, such as conduction of nerve impulses, secretion of hormones and neurotransmitters, and maintaining cardiac rhythm. My recent work has been focused on two types of ion channels, the CLC chloride channels (CLC, for Cl- Channels) and cyclic nucleotide-gated (CNG) channels.
The CLC-type channels carry out a variety of physiological tasks. For example, the CLC-1 chloride channel controls the membrane potential and the excitability of muscle cells, and certain myotonias in goats, mice, and humans are caused by its disruption. CLC-2, another member in this family, is expressed ubiquitously in various tissues. Mutation of CLC-2 gene is underlying one form of idiopathic epilepsy. On the other hand, CNG channels play critical roles in sensory signal transductions in vertebrate and invertebrate species. CNG channels in C. elegans, for example, are important for the olfactory and thermal sensations of the worm. The CNG channels in vertebrate photoreceptors and in olfactory neurons are essential for the visual and olfactory sensations of vertebrate animals, respectively. We recently showed that the CNG channel is inhibited directly by odorants. This odorant inhibition effect of CNG channels may be underlying the olfactory masking phenomenon in which the background fragrance can mask unpleasant smells.
The experimental strategy we employed to examine the mutational effects on CLC channels is to combine electrophysiological methods such as patch-clamp recordings, molecular biological tools such as site-directed mutagenesis, and chemical modification methods using thiol-specific modifying reagents. We have also employed imaging techniques such as fluorescence resonance energy transfer (FRET) to conduct experiments. Various researches on the structures and functions of CLC channels and CNG channels are currently ongoing.
Chen T.-Y. (2005) Structure and function of ClC channels. Ann. Rev. Physiol. 67: 809-839.
Zhang X.-D., Li Y., Yu W.-P. and Chen T.-Y. (2006) Roles of K149, G352 and H401 in the channel functions of ClC-0: Testing the predictions from theoretical calculations. J. Gen. Physiol. 127: 435-447.
Chen, T.-Y., Takeuchi H, and Kurahashi T. (2006) Odorant inhibition of the olfactory cyclic nucleotide-gated channel with a native molecular assembly. J. Gen Physiol. 128: 365-371.
Bykova E. A., Zhang X.-D., Chen T.-Y., and Zheng J. (2006) Large movement in the C-terminus of CLC-0 chloride channel during slow gating. Nature Struct & Mol. Biol. 13: 1115-1119.
Tseng P.-Y., Bennetts B., and Chen T.-Y. (2007) Cytoplasmic ATP inhibition of CLC-1 is enhanced by low pH. J. Gen. Physiol. 130: 217-221.
Chen T.-Y., and Hwang, T.-C. (2008) CLC-0 and CFTR: Chloride channels evolved from transporters. Physiol. Rev. 88: 351-387.
Zhang X.-D. Tseng P.-Y., and Chen T.-Y. (2008) ATP inhibition of CLC-1 is controlled by oxidation and reduction. J. Gen. Physiol. 132: 421-428.
Zhang X.-D., Tseng P.-Y., Yu W.-P., and Chen T.-Y. (2009) Blocking pore-open mutants of CLC-0 by amphiphilic blockers. J. Gen. Physiol. 133: 43-58.
Zhang X.-D., and Chen T.-Y. (2009) Amphiphilic blockers punch through a mutant CLC-0 pore. J. Gen. Physiol. 133: 59-68.
Biochemistry and Molecular Biology
Molecular Cellular and Integrative Physiology
Center for Neuroscience
Department of Neurology