Ion channel function and modulation in human disease
Ion channels are an essential class of proteins that underlie rapid signaling, sensation, and movement in our bodies. These proteins form pores in cell membranes that allow charged ions to pass through and create tiny electrical currents that control cellular activity. Our research program investigates how changes in the function of certain ion channels can lead to diseases, or be targeted to treat certain diseases.
Theme 1: Modulation of voltage-gated potassium channels in epilepsy
Epilepsy is a diverse collection of neurological disorders characterized by abnormal electrical activity in the brain leading to seizures. An estimated 50 million people worldwide are affected by some form of epilepsy, and startlingly, 30% of affected individuals are resistant to conventional treatments. We are investigating the detailed mechanism of action of a new class of anti-epileptic drug. Retigabine is the prototypical member of this class, and over the past few years has been approved for use in humans in Europe and North America. Retigabine has a unique mechanism of action : it is the only anti-epileptic drug that activates voltage-gated K+ channels in the brain. The molecular target of retigabine (KCNQ channels, or ‘M’-channels) provide an interesting system to investigate ion channel function and pharmacology, and are an important target for the development of new anti-epileptic drugs.
We are also investigating a poorly understood mechanism of ‘use-dependent activation’ of Kv1.2-containing neuronal potassium channels. This mechanism allows potassium channels to adapt their behavior in response to repetitive stimulation, and may influence how neurons respond to extreme electrical activity during a seizure. Interestingly, mutations in the Kv1.2 potassium channel gene have been linked to severe epileptic encephalopathy, highlighting the essential role of this channel in the regulation of electrical activity.
Theme 2: Genetic forms of diabetes caused by altered electrical activity of pancreatic β-cells.
Appropriate release of insulin in response to ingestion of a meal is also controlled by ion channels. In pancreatic β-cells, an important ion channel class named KATP (because they are regulated by intracellular ATP:ADP) control cellular excitability in response to changes in the metabolic state. Mutations in these channels can lead to inheritable forms of diabetes (too little insulin secretion) or hyperinsulinism (too much insulin secretion). We investigate the function and regulation of KATP channels and the effects of commonly used anti-diabetic drugs on these channels.
Kurata HT. (2016) Emerging complexities of lipid regulation of potassium channels. J Gen Physiol 148(3):201-5. PMID: 27574290.
Wang AW, Yang R and Kurata HT. (2016) Sequence determinants of subtype-specific actions of KCNQ channel openers. J Physiol [Epub ahead of print]. PMID: 27506413.
Baronas VA, Yang R, Vilin YY and Kurata HT. (2016) Determinants of frequency-dependent regulation of Kv1.2-containing potassium channels. Channels (Austin) 10(2):158-66. PMID: 26646078.
Kim RY, Yau MC, Galpin JD, Seebohm G, Ahern CA, Pless SA, Kurata HT. (2015) Atomic basis for therapeutic activation of neuronal potassium channels. Nat Commun 6:8116. PMID: 26333338.
Zhang RS, Wright JD, Pless SA, Nunez JJ, Kim RY, Li JB, Yang R, Ahern CA, Kurata HT. (2015) A Conserved Residue Cluster That Governs Kinetics of ATP-dependent Gating of Kir6.2 Potassium Channels. J Biol Chem 290(25):15450-61. PMID: 25934393.
Baronas VA, McGuinness BR, Brigidi GS, Gomm Kolisko RN, Vilin YY, Kim RY, Lynn FC, Bamji SX, Yang R, Kurata HT. (2015) Use-dependent activation of neuronal Kv1.2 channel complexes. J Neurosci 35(8):3515-24. PMID: 25716850.
Pless SA, Kim RY, Ahern CA, Kurata HT. (2015) Atom-by-atom engineering of voltage-gated ion channels: Magnified insights into function and pharmacology. J Physiol 2015 Jan 30. [Epub ahead of print]. PMID: 25640301.
Pless SA, Elstone FD, Niciforovic AP, Galpin JD, Yang R, Kurata HT, Ahern CA. (2014) Asymmetric functional contributions of acidic and aromatic side chains in sodium channel voltage-sensor domains. J Gen Physiol 143(5):645-56. PMID: 24778431.
Yang YH, Vilin YY, Roberge M, Kurata HT, Johnson JD. (2014) Multiparameter screening reveals a role for Na+ channels in cytokine-induced β-cell death. Mol Endocrinol 28(3):406-17. PMID: 24438339.
Baronas VA, Kurata HT. (2014) Inward rectifiers and their regulation by endogenous polyamines. Front Physiol 5:325. PMID: 25221519.
Bruin JE, Erener S, Vela J, Hu X, Johnson JD, Kurata HT, Lynn FC, Piret JM, Asadi A, Rezania A, Kieffer TJ. (2014) Characterization of polyhormonal insulin-producing cells derived in vitro from human embryonic stem cells. Stem Cell Res 12(1):194-208. PMID: 24257076.
Pless SA, Galpin JD, Niciforovic AP, Kurata HT, Ahern CA. (2013) Hydrogen bonds as molecular timers for slow inactivation in voltage-gated potassium channels. Elife 2:e01289. PMID: 24327560.
Vilin YY, Nunez JJ, Kim RY, Dake GR, Kurata HT. (2013) Paradoxical activation of an inwardly rectifying potassium channel mutant by spermine: "(b)locking" open the bundle crossing gate. Mol Pharmacol 84(4):572-81. PMID: 23887925.
Li JB, Huang X, Zhang RS, Kim RY, Yang R, Kurata HTD (2013) Decomposition of slide helix contributions to ATP-dependent inhibition of Kir6.2 channels. J Biol Chem 288(32):23038-49. PMID: 23798684.
Sala-Rabanal M, Li DC, Dake GR, Kurata HT, Inyushin M, Skatchkov SN, Nichols CG. (2013) Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3. Mol Pharm 10(4):1450-8. PMID: 23458604.