Pharmacology

Harley T Kurata

Dr Harley T Kurata

Associate Professor

Education:
BSc, University of British Columbia, 1999
PhD, University of British Columbia, 2004

Teaching: PMCOL425/525

Research: Mechanisms of chronic pain after CNS injury or disease

Research Interests / Laboratory Techniques

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. We investigate the molecular target of retigabine (KCNQ channels, or ‘M’-channels) in order to accelerate the development of new anti-epileptic drugs, and develop our understanding of how mutations in these channels are linked to seizure disorders.

Theme 2: Ion channel regulation in multi-protein complexes

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. We use this as a model system to investigate assembly of ion channels into multi-protein complexes. We recently identified Slc7a5 (LAT1) as a powerful regulator of Kv1.2 expression and activity. This is of great interest to us, because mutations in both Kv1.2 and Slc7a5 are linked to neurological diseases, and manyl epilepsy-linked Kv1.2 mutations exhibit hypersensitivity to the effects of Slc7a5. We are also actively investigating a number of other regulatory mechanisms identified from unbiased mass spectrometry screens of voltage-gated potassium channel complexes.

Selected Recent Publications

Baronas, V.A.,Yang, R.Y., Morales, L.C., Sipione, S., and H.T. Kurata. 2018. Slc7a5 regulators Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations. Nature Communications. 9(1):4417. PMID: 30356053

Wang,C.K., Lamothe, S.M. Wang,A.W., Yang,R.Y., H.T. Kurata. 2018.State-dependent actions of pore and voltage sensor targeted KCNQ openers. J. Gen Physiol. PMID: 30373787

Yau, M.C., Kim, R.Y., Wang,C.K., Li, J., Ammar, T.E., Yang,R.Y., Pless, S.A., H.T. Kurata. 2018. One drug-sensitive subunit is sufficient for a near-maximal retigabine effect in KCNQ channels. J. Gen Physiol. 150(10):1421-1431. PMID: 30166314.

Wang,A.W., Yau, M.C., Wang,C.K., Sharmin,N., Yang,R.Y., Pless, S.A., †H.T. Kurata. 2018. Functional stoichiometry of KCNQ channel openers II: voltage sensor-targeted openers. J. Gen Physiol. 150(10):1432-1443. PMID: 30166313.

Kim, R.Y., Pless, S.A., and H.T. Kurata. 2017. PIP2 mediates functional coupling and pharmacology of neuronal KCNQ channels. PNAS. 114(45):E9702- E9711. PMID: 29078287

Baronas, V.A., Yang, R.Y., and H.T. Kurata. 2017. Extracellular redox sensitivity of Kv1.2 potassium channels. Sci. Rep. 7(1):9142. PMID: 28831076

Wrobel, E., Rothenberg, I., Krisp, C., Hundt, F., Fraenzel, B., Eckey, K., Linders, J.T., Gallacher, D.J., Towart, R., Pott, L., Pusch, M., Yang, T., Roden, D.M., Kurata, H.T., Schulze-Bahr, E., Strutz-Seebohm N., Wolters, D., and Seebohm, G. 2016. KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmalogical targeting. Nature Communications. 7:12795. PMID: 27731317.

Wang, A.W., Yang, R., and H.T. Kurata. 2016. Sequence determinants of subtype-specific actions of KCNQ channel openers. J. Physiol. Epub August 9, 2016. PMID: 27506413.

Kim, R.Y., Yau, M., Galpin, J.D., Ahern, C.A., Pless, S.A., and H.T. Kurata. 2015. Atomic basis for therapeutic activation of neuronal potassium channels. Nature Communications. 6:8116. PMID: 26333338.

Baronas, V., McGuinness, B.R., Brigidi, G.S., Gomm Kolisko, R.H., Vilin, Y.Y., Kim, R.Y., Lynn, F.C., Bamji, S.X., Yang, R.Y. and H.T. Kurata. 2015. Use-dependent activation of neuronal Kv1.2 channel complexes. J. Neurosci. 35(8):3515:3524. PMID: 25716850.