Alan L. Goldin
M.D./Ph.D., University of Michigan, 1983
University of California,
Irvine
Medical Sciences I,
Irvine, CA 92697-4025
(949) 824-5334
agoldin@uci.edu
UCI
Faculty Profile:Alan L. Goldin
Neurobiology, Cell Biology and Structural Biology & Molecular Biophysics
Diseases Caused by Ion Channel Defects.
Our lab is studying the effects of mutations in ion channels to
determine how specific alterations in channel function are manifested
in the central nervous system. It has already been shown that two type
of human diseases result from mutations in sodium channels. The periodic
paralyses result from alterations in skeletal muscle sodium channels,
and long QT syndrome results from mutations in the cardiac channel. Our
goals are to determine how sodium channel mutations in the central nervous
system cause disease. We are using three approaches. First, we are studying
the effects of spontaneous mutations in mice. For example, jolting results
from a single amino acid change in a sodium channel expressed in the cerebellum,
causing ataxia and involuntary movements. We have shown that these effects
are caused by a change in the voltage-dependence of the channel. The second
approach is to construct transgenic mice expressing sodium channels with
well-defined mutations. We have expressed a channel with incomplete inactivation
in the CNS of mice, which resulted in epilepsy and early mortality. The
picture on the right shows a mouse expressing this channel to demonstrate
the stereotyped movement disorder resulting from the seizures, and the
electroencephalographic trace underneath demonstrates the rapid and continuous
electrical firing. The third approach is to identify candidate mutations
in humans, and then examine the effects of those mutations by constructing
transgenic mice. We have analyzed the effects of mutations that cause
Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and have shown
that 4 different mutations all have different effects on channel function.
Despite these differences, there are similarities in the effects of these
mutations on neuronal firing in computer simulations. We are now
testing the predictions of those simulations by expressing the mutations
in primary neuronal cells and by constructing transgenic mice.
A second area of interest is the cell biology of ion channels.
There are multiple different sodium channel isoforms, including at least
four that are expressed in the CNS. These subtypes are localized in different
regions of the CNS, and in different intracellular locations. We are interested
in determining the functional significance of those differences, using
a variety of approaches. We have constructed full-length functional clones
of the channels, and we are examining the properties of those channels
in Xenopus oocytes. We then compare those properties with the sodium currents
observed in vivo, to determine how different subtypes are responsible
for different conductances. In addition, we are examining the localization
of the different subtypes by constructing channels containing different
synthetic epitopes, and then using antibodies against the epitopes to
identify each of the channel types. The channels are expressed both in
tissue culture cell lines and in transgenic mice to examine intracellular
and regional localization.
There are three other areas of interest in the lab. First, we are
examining the correlation between structure and function in ion channels
by constructing specific mutations and determining the electrophysiological
effects of those mutations. These studies have identified one region of
the sodium channel as functioning as an intracellular loop that causes
inactivation, and demonstrated that this loop interacts with another region
of the channel during the inactivation process. Second, we are studying
the interactions between antiarrhythmic drugs and sodium channels. Many
of these drugs reduce the incidence and severity of cardiac arrhythmias
by blocking sodium channels, and we are identifying the molecular sites
of interaction between the drugs and the channel with the goal of developing
more specific antiarrhythmic agents. Third, we are examining ion channel
modulation, particularly with respect to phosphorylation by protein kinase
A. These studies have shown that sodium currents are decreased by PKA
phosphorylation at one specific site, which is both necessary and sufficient
modulation. The reduction in current occurs because of the negative charge
resulting from phosphorylation.
For further information, please see the Goldin
Lab Home Page.
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.
Catterall, W.A., Goldin, A.L. and Waxman, S.G. 2005. International Union
of Pharmacology. XLVII. Nomenclature and structure-function relationships
of voltage-gated sodium channels. Pharmacol. Rev. 57:397-409.
Goldin, A.L. 2006. Ion channel disorders, in Neurobiology of Disease, ed.
Gilman, S., Elsevier, San Diego, 135-148.
Goldin, A.L. 2007. Neuronal channels and receptors, in Molecular
Neurology, ed. Waxman, S.G., Elsevier, San Diego, 43-58.
Goldin, A.L. 2006. Expression of ion channels in Xenopus oocytes, in
Expression and Analysis of Recombinant Ion Channels, eds. Clare, J.J. and
Trezise, D.J., Wiley-VCH, Weinheim, 1-25.
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 GEFS+ mutation in the sodium channel SCN1A identifies a cytoplasmic domain for b 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.
Li, R.A., I.L. Ennis, T. Xue, H.M. Nguyen, G.F. Tomaselli, A.L. Goldin and E. Marban. 2003. Molecular basis of isoform-specific m-conotoxin block of cardiac, skeletal muscle, and brain Na+ channels. J. Biol. Chem. 278:8717-8724.
Spampanato, J., A. Escayg, M.H. Meisler and A.L. Goldin. 2003. The generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage-dependent gating of Nav1.1 sodium channels. Neurosci. 116:37-48.
Tan, J., Z. Liu, Y. Nomura, A.L. Goldin and K. Dong. 2002. Alternative splicing of an insect sodium channel gene generates pharmacologically distinct sodium channels. J. Neurosci. 22:5300-5309.
Spampanato, J., A. Escayg, M.H. Meisler and A.L. Goldin. 2001. Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2. J. Neurosci. 21:7481-7490.
Goldin, A.L. 2001. Resurgence of sodium channel research. Annu. Rev. Physiol., 63:871-894.
Goldin, A.L., R.L. Barchi, J.H. Caldwell, F. Hofmann, J.R. Howe, J.C.
Hunter, R.G. Kallen, G. Mandel, M.H. Meisler, Y. Berwald-Netter, M. Noda,
M.M. Tamkun, S.G. Waxman, J.N. Wood and W.A. Catterall. 2000. Nomenclature
of voltage-gated sodium channels. Neuron 28:365-368.
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.
List
of Publications via PubMed (NIH National Library of Medicine)