Ion Channels and Central Nervous System Disease
Lucille P. Markey Scholar
Fellow of the American Heart Association
Fellow of the American Epilepsy Society
National Multiple Sclerosis Society Fellow, Department of Biology, Caltech
Dr. Goldin investigates the role of voltage-gated sodium channels in the pathophysiology and therapy of epilepsy, with two aspects. The first is to determine how human sodium channel mutations cause epilepsy by using mouse models and induced pluripotent stem cells (iPSCs). To study the effects in mice, Dr. Goldin and his collaborators have constructed both transgenic and knock-in mouse models of the human epilepsy syndromes Genetic Epilepsy with Febrile Seizures Plus (GEFS) and Dravet Syndrome, both of which are caused primarily by mutations in one of the CNS sodium channels. They are studying the seizure susceptibility of the mice and the effects of the mutations on sodium channel properties, neuronal cell firing, and network excitability in the hippocampus. To study the effects in iPSCs, they are preparing cells from a patient with GEFS and a control sibling, differentiating the cells into neurons, and then comparing the properties of those neurons with hippocampal neurons from a knock-in mouse expressing the same mutation. The second aspect is to determine the therapeutic potential of sodium channel inhibitors and activators for epilepsy. Dr. Goldin and his collaborators have demonstrated that decreased function of one specific sodium channel isoform leads to decreased seizure susceptibility and can partially correct the defect of another sodium channel mutation that causes epilepsy. They are now examining compounds to identify ones that selectively activate or inhibit specific sodium channel isoforms. The compounds will then be tested for their efficacy in preventing seizures in a variety of mouse models of epilepsy.
UCI Health Science Partners Circle of Excellence Award
Athalie Clark Excellence in Research Award
Pugsley, M.K., S.L. Yong, A.L. Goldin, E.S. Hayes, M.J.A. Walker. 2019. Molecular charge associated with antiarrhythmic actions in a series of amino-2-cyclohexyl ester derivatives. Eur. J. Pharmacol. 844:241-252. PMCID: in progress.
Walker, M.J.A., E.S. Hayes, D.A. Saint, G. Adaikan, S. Abraham, A.L. Goldin, G.N. Beatch, B.A. MacLeod, R.A. Wall and M.K. Pugsley. 2018. Pharmacological and toxicological activity of RSD921, a novel sodium channel blocker. Biomed. Pharmacother. 106:510-522. PMCID: PMC6492542.
Dutton, S.B.B., K. Dutt, L.A. Papale, S. Helmers, A.L. Goldin and A. Escayg. 2017. Early-life febrile seizures worsen adult phenotypes in Scn1a mutants. Exp. Neurol. 293:159-171. PMCID: PMC5538963.
Makinson, C.D., B.S. Tanaka, J.M. Sorokin, J. Wong, C. Christian, A.L. Goldin, A. Escayg and J.R. Huguenard. 2017. Regulation of thalamic and cortical network synchrony by Scn8a. Neuron 93:1165-1179. PMCID: PMC5393918.
Makinson, C.D., K. Dutt, F. Liu, L.A. Papale, A. Shankar, A.J. Barela, R. Liu, A.L. Goldin and A Escayg. 2016. An Scn1a epilepsy mutation in Scn8a alters seizure susceptibility and behavior. Exp. Neurol. 275:46-58. PMCID: PMC4688066.
Coleman, N., H.M. Nguyen, Z. Cao, B.M. Brown, D.P. Jenkins, D. Zolkowska, Y.-J. Chen, B.S. Tanaka, A.L. Goldin, M.A. Rogawski, I.N. Pessah and H. Wulff. 2014. The riluzole derivative 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a mixed KCa2 activator and Nav blocker, is a potent novel anticonvulsant. Neurotherapeutics 12:234-249.
Makinson, C.D., B.S. Tanaka, T. Lamar, A.L. Goldin* and A. Escayg*. 2014. Role of the hippocampus in Nav1.6 (Scn8a) mediated seizure resistance. Neurobiol. Dis. 68:16-25.
Gao, R., Y. Du, L. Wang, Y. Nomura, G. Satar, D. Gordon, M. Gurevitz, A.L. Goldin and K. Dong. 2014. Sequence variations at I260 and A1731 contribute to persistent currents in Drosophila sodium channels. Neuroscience 268:297-308.
Lioudyno, M.I., A.M. Birch, B.S. Tanaka, Y. Sokolov, A.L. Goldin, K.G. Chandy, J.E. Hall and M.T. Alkire. 2013. Shaker-related potassium channels in the central medial nucleus of the thalamus are important molecular targets for arousal suppression by volatile general anesthetics. J. Neurosci. 33:16310-16322.
Nugyen, H.M., H. Miyazaki, N. Hoshi, B.J. Smith, N. Nukina, A.L. Goldin and K.G. Chandy. 2012. Modulation of voltage-gated K+ channels by the sodium channel ?1 subunit. Proc. Natl. Acad. Sci. USA. 109:18577-18582.
Song, W., Y. Du, Z. Liu, N. Luo, M. Turkov, D. Gordon, M. Gurevitz, A.L. Goldin and K. Dong. 2011. Mutations in the domain III voltage sensing module enhance the sensitivity of an insect sodium channel to a scorpion beta-toxin. J. Biol. Chem. 286:15781-15788.
Martin, M.S., K. Dutt, L.A. Papale, C.M. Dubé, S.B. Dutton, G. de Haan, A. Shankar, S. Tufik, M.H. Meisler, T.Z. Baram, A.L. Goldin* and A. Escayg*. 2010. Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities. J. Biol. Chem. 285:9823-9834. *Co-corresponding authors.
Nguyen, H.M. and A.L. Goldin. 2010. Sodium channel carboxy terminal residue regulates fast inactivation. J. Biol. Chem. 285:9077-9089.
Lee, A. and A.L. Goldin. 2009. Role of the terminal domains in sodium channel localization. Channels 3:171-180.
Tang, B., K. Dutt, L. Papale, R. Rusconi, A. Shankar, J. Hunter, S. Tufik, F.H. Yu, W.A. Catterall, M. Mantegazza, A.L. Goldin* and A. Escayg*. 2009. A BAC transgenic mouse model reveals neuron subtype-specific effects of a Generalized Epilepsy with Febrile Seizures Plus (GEFS+) mutation. Neurobiol. Dis. 35:91-102. *Co-corresponding authors.
Lee, A. and A.L. Goldin. 2008. Role of the amino and carboxy termini in isoform-specific sodium channel variation. J. Physiol. 586:3917-3926.
Jang, G.M., B. Tanaka, G.A. Gutman, A.L. Goldin and B.L. Semler. 2008. Alternative polyadenylation signals in the 3’ noncoding region of a voltage-gated potassium channel gene are major determinants of mRNA isoform expression. Gene 408:133-145.
Ehrengruber, M.U. and A.L. Goldin. 2007. Semliki Forest Virus vectors with mutations in the nonstructural protein 2 gene permit extended super-infection of neuronal and non-neuronal cells. J. Neurovirol. 13: 353-363.
Barela, A.J., S.P. Waddy, J.G. Lickfett, J. Hunter, A. Anido, S.L. Helmers, A.L. Goldin and A. Escayg. 2006. An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability. J. Neurosci. 26:2714-2723.
Zhou, W. and A.L. Goldin. 2004. Use-Dependent Potentiation of the Nav1.6 Sodium Channel. Biophys. J. 87:3862-3872.
Spampanato, J., J.A. Kearney, G. de Haan, D.P. Mc Ewen, A. Escayg, I. Aradi, B.T. MacDonald, S.I. Levin, I. Soltesz, P. Benna, E. Montalenti, L.L. Isom, A.L. Goldin and M.H. Meisler. 2004. A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for beta subunit interaction. J. Neurosci. 24:10022-10034.
Zhou, W., I. Chung, Z. Liu, A.L. Goldin and K. Dong. 2004. A voltage-gated calcium-selective channel encoded by a sodium channel-like gene. Neuron 42:101-112.
Spampanato, J., I. Aradi, I. Soltesz and A.L. Goldin. 2004. Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus. J. Neurophysiol. 91:2040-2050.
Goldin, A.L. 2003. Mechanisms of sodium channel inactivation. Curr. Opinion Neurobiol. 13:284-290.
Spampanato, J., A. Escayg, M.H. Meisler and A.L. Goldin. 2003. Generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage-dependent gating of Nav1.1 sodium channels. Neurosci. 116:37-48.
Goldin, A.L. 2001. Resurgence of sodium channel research. Annu. Rev. Physiol. 63:871-894.
Kearney, J.A., N.W. Plummer, M.R. Smith, J. Kapur, T.R. Cummins, S.G. Waxman, A.L. Goldin and M.H. Meisler. 2001. A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neurosci. 102:307-317.
Escayg, A. and A.L. Goldin. 2010. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 51:1650-1658.
National Institutes of Health - "A Novel Target for the Treatment of Temporal Lobe Epilepsy"
National Institutes of Health – “Medical Scientist Training Program”
Society for Neuroscience
American Epilepsy Society
American Society for Cell Biology
American Association for the Advancement of Science
Senior Research Fellow
California Institute of Technology 1983—1988
Structural Biology and Molecular Biophysics
Interdepartmental Neuroscience Program