Harley T Kurata

Teaching: PMCOL425/525

Research: Mechanisms of chronic pain after CNS injury or disease

Research Interests / Laboratory Techniques

Theme 1: Modulation of voltage-gated potassium channels for the treatment of 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), and other drugs that are thought to target the voltage-sensing domain of these channels. We hope this work will 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. We hope this work will reveal unrecognized complexity in the organization and regulation of ion channels involved in signal transmission in the brain.

Selected Recent Publications

1. Yang ND, Kanyo R, Zhao L, Li J, Kang PW,  Dou AK, McFarland-White K, Shi J, Nerbonne JM, Kurata HT†, Cui J†. 2022. Electro-mechanical coupling of KCNQ channels is a target of epilepsy-associated mutations and retigabine. Science Advances

2. Lamothe SM, Sharmin N, Silver G, Satou M, Hao Y, Tateno T, Baronas VA, Kurata HT†. Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels. Elife. 2020 Nov 9;9. doi: 10.7554/eLife.54916. PubMed PMID: 33164746

3. Li J, Maghera J, Lamothe SM, Marco EJ, H.T. Kurata†. 2020. Heteromeric assembly of truncated neuronal Kv7 channels: implications for neurological disease and pharmacotherapy. Mol Pharmacol. Jun 24; PMID: 32580997. 

4. Lamothe SM, H.T. Kurata†. 2020 Slc7a5 alters Kvβ-mediated regulation of Kv1.2. J Gen Physiol. Jul 6;152(7). PMID: 32311044.

5. Kanyo R, Wang CK, Locskai LF, Li J, Allison WT, H.T. Kurata†. 2020. Functional and behavioral signatures of Kv7 activator drug subtypes. Epilepsia. 2020 Jul 11; PMID: 32652600.

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

7. 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. 150(12):1722-1734. PMID: 30373787.

8. 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.

9. Wang,A.W., Yau, M.C., Wang,C.K., Sharmin,N., Yang,R.Y., Pless, S.A., †H.T. Kurata. 2018. Four drug-sensitive subunits are required for maximal effect of a voltage sensor-targeted KCNQ opener. J. Gen Physiol. 150(10):1432-1443. PMID: 30166313.

10. 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

11. 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

12. 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.