Haijun Chen

Areas of Interest

• Molecular properties of ion channels and signaling in the cell membrane
• Molecular mechanisms of potassium channel function
• Inter-subunit interactions of potassium channel complexes
• Protective effects of Potassium channels during ischemia
• Regulation of synaptic function in epilepsy

Research

Goal:
Ion channels are membrane proteins which allow ions across cell membranes in response to physical and/or chemical stimulations. They play a key role in electrical signaling of excitable cells such as neurons and cardiac myocytes. Dysfunction of ion channels could cause human neuronal, muscular, and cardiac disorders such as arrhythmia and epilepsy. Our goals are to understand how several subfamilies of potassium channels (Fig.1) are gated and regulated in physiological and pathological conditions.
 

Overview:

Background K+ channels in hypokalemia. Hypokalemia refers to lower-than-normal serum potassium (K+) concentrations. Moderate hypokalemia may cause muscular weakness, muscle cramps, cardiac arrhythmias. More severe hypokalemia may result in flaccid paralysis, cardiac arrest and paralysis of the lungs. According to Emergency Medicine, hypokalemia is clinically significant in as many as 0.8%-1% of hospitalized patients in USA. Several types of muscles can unexpectedly become depolarized in hypokalemia. Although this well-known phenomenon is the key to understand the pathological mechanism of hypokalemic periodic paralysis, the most frequent form of heritable periodic paralysis, its mechanism is not yet known. We attempt to study the function of background K+ channels in muscle cells and elucidate the molecular mechanism of paradoxical depolarization.

Na+-activated K+ channels in ischemia. Na+-activated K+ channels potassium channels highly express in the brain and heart, but its physiological role is not well understood. It was generally assumed that these channels protect neurons and cardiac cells from hypoxic injury during ischemia. We are interested in understanding molecular properties of these channels and how they contribute cardiac excitability and play an important role in cardio-protection.

Voltage-gated K+ channels in epilepsy. A novel protein was recently found to associate with inherited epilepsy, and it functions as a neurotransmitter. We are interested in elucidating molecular mechanisms how this protein regulates synaptic transmission and why its mutations can cause epilepsy. We hypothesize that this protein targets one accessory subunit of voltage-gated potassium channel complexes highly expressed in post-synapse, changes biophysical properties of these potassium channels, and then alters excitability of post-synapse. We will examine this hypothesis in both the expression system and brain slices.
 

Approach:

We mainly use patch-clamp and two-electrode voltage-clamp techniques to record gating currents, single channel currents, macroscopic currents, whole-cell currents, resting potentials, and action potentials from the expression systems or native tissues, though we employ multidisciplinary approaches (molecular biology, protein biochemistry, immunocytochemical staining, fluorescence imaging, and knockout mouse strategy) to strengthen our research.

Publications

• Chen K, Zuo D, Wang S, Chen H* (2018). Kir2 inward rectification-controlled precise and dynamic balances between Kir2 and HCN currents initiate pacemaker activity. FASEB Journal (In Press).
• Xiong J, Liu X, Gong Y, Zhang P, Qiang S, Zhao Q, Guo R, Qian Y, Wang L, Zhu L, Wang R, Hao Z, Wen H, Zhang J, Tang K, Zang WF, Yuchi Z, Chen H, Chen SRW, Zheng W, Wang SQ, Xu YW, Liu Z* (2018) Pathogenic mechanism of a catecholaminergic polymorphic ventricular tachycardia causing-mutation in cardiac calcium release channel RyR2. Journal of Molecular and Cellular Cardiology (In press).
• Chen K, Zuo D, Liu Z, Chen H* (2017). Kir2.1 channels set two levels of resting membrane potential with inward rectification. Pflugers Arch: European Journal of Physiology. 2018, 470(4): 599-611.
• Zuo D, Chen K, Zhou M, Liu Z, Chen H (2017). Kir2.1 and K2P1 channels reconstitute two levels of resting membrane potential in cardiomyocytes. Journal of Physiology-London. 2017, 595(15): 5129-5142 
• Wang W, Kiyoshi CM, Du Y, Ma B, Alford CC, Chen H & Zhou M. (2016). mGluR3 Activation Recruits Cytoplasmic TWIK-1 Channels to Membrane that Enhances Ammonium Uptake in Hippocampal Astrocytes. Molecular neurobiology. 2016, 53(9):6169-6182. PubMed PMID: 26553349
• Du Y, Kiyoshi CM, Wang Q, Wang W, Ma B, Alford CC, Zhong S, Wan Q, Chen H, Lloyd EE, Bryan RM, Jr., Zhou M. (2016) Genetic Deletion of TREK-1 or TWIK-1/TREK-1 Potassium Channels does not Alter the Basic Electrophysiological Properties of Mature Hippocampal Astrocytes In Situ. Frontiers in Cellular Neuroscience. 2016;10:13. doi: 10.3389/fncel.2016.00013. PubMed PMID: 26869883; PubMed Central PMCID: PMC4738265.
• Chen H, Zuo D, Zhang J, Zhou M, and Liqun Ma (2014) Classification of two-pore domain potassium channels based on rectification under quasi-physiological ionic conditions. Channels. In press.
• Chen H, Chatelain FC, Lesage F (2014) Altered and dynamic ion selectivity of K+ channels in cell development and excitability. Trends in Pharmacological Sciences 35(9): 461-469.
• Wang, W., A. Putra, G. P. Schools, B. Ma, H. Chen, L. K. Kaczmarek, J. Barhanin, F. Lesage, and M. Zhou (2013) The contribution of TWIK-1 channels to astrocyte K(+) current is limited by retention in intracellular compartments. Frontiers in cellular neuroscience 7:24.
• Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, Chen H, Kronengold J,  Abhyankar A, Cilio R, Nitschke P, Kaminska A, Boddaert N, Casanova JL, Desguerre I, Munnich A, Dulac O, Kaczmarek LK, Colleaux L, Nabbout R (2012). De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nature genetics. 2012;44(11):1255-9. 
• Ma L, Zhang X, Zhou M, Chen H (2012) Acid-sensitive TWIK and TASK potassium channels change ion selectivity and become permeable to sodium in extracellular acidification. Journal of Biological Chemistry 287: 37145-37153.
• Ma L, Xie Y, Zhou M,Chen H (2012) Silent TWIK-1 potassium channels conduct monovalent cation currents. Biophysical Journal 102:L34-L36.
• Ma, L., Zhang, X. and Chen, H. (2011) TWIK-1 Two-Pore Domain Potassium Channels Change Ion Selectivity and Conduct Inward Leak Sodium Currents in Hypokalemia. Science Signaling, 4(176), ra37. [abstract] [full text] [pdf reprint][featured in]
• Gazula VR, Strumbos JG, Mei X, Chen H, Rahner C, Kaczmarek LK (2010). Localization of Kv1.3 channels in presynaptic terminals of brainstem auditory neurons. Journal of Comparative Neurology. 518(16):3205-20. 
• Zhou, M., Xu,G., Xie, M, Zhang, X., Schools, G.P., Ma, L., Kimelberg, H.K., and Chen, H. (2009)TWIK-1 and TREK-1 are potassium channels contributing significantly to astrocyte passive conductance in rat hippocampal slices. Journal of Neuroscience 29(26): 8551-8564
• Chen, H., Kronengold, J., Yan, J., Gazula, V.R., Ferreira, G., Yang, Y., Bhattacharjee, A., Sigworth, F.J., Salkoff, L., and Kaczmarek, L.K. (2009) The N-terminal domain of Slack determines the formation and functional expression of Slick/Slack heteromeric sodium-activated potassium channels. Journal of Neuroscience. 29(17): 5654-5665 
• Chen H. and Goldstein S. A. (2007) Serial perturbation of MinK in IKs implies an α-helical transmembrane span traversing the channel corpus. Biophysical Journal, 93(7): 2332-40.
• Chen H., C. von Hehn, L.K. Kaczmarek, L. R. Ment, B.R. Pober, and F.M. Hisama. (2007) Functional Analysis of a Novel Potassium Channel (KCNA1) Mutation in Hereditary Myokymia. Neurogenetics8(2):131-5.
• Sun, A.-Q., Balasubramaniyan N., Chen H., M. Shahid M., Suchy FJ. (2006). Identification of functionally relevant residues of the rat ileal apical sodium dependent bile acid cotransporter (rASBT). Journal of Biological Chemistry 281, 16410-8.
• Barbier, J., Lamthanh, H., Le Gall F., Favreau P., Benoit E., Chen, H., Gilles N., Ilan N., Heinemann, S.H., Gurevitz M., Gordon D., Ménez A., and Molgó, J. (2004). A δ-conotoxin from Conus ermineusvenom inhibits inactivation in vertebrate neuronal Na+ channels, but not in skeletal and cardiac muscles. Journal of Biological Chemistry 279, 4680-4685.
• Chen H. Kim, L.A., Rajan S., Xu S., and Goldstein, S. A. (2003). Charybdotoxin binding in the IKs pore demonstrates two MinK subunits in each channel complex. Neuron 40, 15-23.
• Chen, H., Sesti, F., and Goldstein, S. A. (2003). Pore- and State-Dependent Cadmium Block of IKs Channels Formed with MinK-55C and Wild-Type KCNQ1 Subunits. Biophysical Journal 84, 3679-3689.
• Chen, H., Lu, S., Leipold, E., Gordon, D., Hansel, A., and Heinemann, S. H. (2002). Differential sensitivity of sodium channels from the central and peripheral nervous system to the scorpion toxins Lqh-2 and Lqh-3. European Journal of Neuroscience 16, 767-770.
• Chen, H., and Heinemann, S. H. (2001). Interaction of scorpion alpha-toxins with cardiac sodium channels: binding properties and enhancement of slow inactivation. Journal of General Physiology117, 505-518.
• Gilles, N., Leipold, E., Chen, H., Heinemann, S. H., and Gordon, D. (2001). Effect of depolarization on binding kinetics of scorpion alpha-toxin highlights conformational changes of rat brain sodium channels. Biochemistry 40, 14576-14584.
• Chen, H., Gordon, D., and Heinemann, S. H. (2000). Modulation of cloned skeletal muscle sodium channels by the scorpion toxins Lqh II, Lqh III, and Lqh alphaIT. Pflugers Arch: European Journal of Physiology 439, 423-432.
• Gilles, N., Chen, H., Wilson, H., Le Gall, F., Montoya, G., Molgo, J., Schonherr, R., Nicholson, G., Heinemann, S. H., and Gordon, D. (2000). Scorpion alpha and alpha-like toxins differentially interact with sodium channels in mammalian CNS and periphery. European Journal of Neuroscience 12, 2823-2832.
• Chen, H., Kubo, Y., Hoshi, T., and Heinemann, S.H. (1998). Cyclosporin A selectively reduces functional expression of Kir2.1 potassium channels in Xenopus oocytes. FEBS letters 422, 307-310.