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Ion channel proteins: Structure and function.
Our work is directed towards understanding
how ion channels operate in health and illness. These integral membrane
proteins catalyze the selective transfer of ions across membranes and,
like enzymes, show exquisite specificity and tight regulation. As a
class, ion channels orchestrate electrical signals that allow excitation
of central and peripheral nerves, cardiac and skeletal muscle, and even
circulating lymphocytes; less sensational but equally important, ion
channels mediate fluid and electrolyte homeostasis. Remarkably, our
most fundamental questions remain to be answered. What are the structural
bases for their operation? How do inherited mutations and polymorphisms
produce disease? How do drugs act on ion channels to yield beneficial
outcomes in some patients and unwanted side-effects in others? We apply
genetic, biophysical, biochemical, and structural methods to pursue
the normal role, disease-association, and structural basis for function
of potassium channels in five areas: (1) Potassium channel pore-forming
subunits. (2) Potassium channel accessory subunits. (3) Diseases of
potassium channels in heart, skeletal muscle and kidney. (4) The 3D
structure of potassium channels. (5) Potassium channel structure and
function dissected with yeast molecular genetics.
 Figure
caption:
Potassium channel molecular architecture.
Current model of Shaker-type voltage-gated K+ channels showing
tetrameric assembly and transmembrane topology. Regions involved in
specific channel functions include the "ball and chain" inactivation
domain, "S4" voltage-sensing domain, pore-forming region and
charybdotoxin (CTX) receptor. The sequence in the Shaker channel
forming the CTX receptor is expanded.
Recent publications:
Federico
Sesti, Sindhu Rajan, Rosana Gonzalez-Colaso, Natalia Nikolaeva, and
S. A. N. Goldstein. Hyperpolarization
moves S4 sensors inward to open MVP, a methanococcal voltage-gated potassium
channel. Nature Neurosci. 6:353-361.2003
O'Kelly,
I., Butler, M.H., Zilberberg, N. and S. A. N. Goldstein. Forward
Transport: 14-3-3 binding overcomes dibasic retention in endoplasmic
reticulum by dibasic signals. Cell. 111:577-588.2002
Abbott,
G. W. and S. A. N. Goldstein. Disease-associated
mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous
disruption of multiple currents and conservation of mechanism. FASEB
J. 16:390-400.2002
Zilberberg,
N., Ilan, N., and S.A.N. Goldstein.
KCNKØ: Opening and closing the 2-P-domain potassium leak channel entails
"C-type" gating of the outer pore. Neuron. 32:635-648.2001
Goldstein,
S.A.N., Bockenhauer, D., O'Kelly, I. and N. Zilberberg. Potassium
leak channels and the KCNK family of two-P-domain subunits. Nature
Rev Neurosci. 2:175-184.2001
Abbott,
G. W., Butler, M. H., Bendahhou, S., Dalakas, M. C., Ptacek, L. J.,
and S. A. N. Goldstein. MiRP2
forms potassium channels in skeletal muscle with Kv3.4 and is associated
with periodic paralysis. Cell. 104:217-231.2001
Sesti
F, Shih TM, Nikolaeva N, Goldstein SA.
Immunity to K1 killer toxin: internal TOK1 blockade. Cell. 2001
Jun 1;105(5):637-44.
Lopes CM, Zilberberg N, Goldstein SA. Block of Kcnk3 by protons. Evidence
that 2-P-domain potassium channel subunits function as homodimers.
J Biol Chem. 2001 Jul 6;276(27):24449-52.
Abbott GW, Goldstein SA, Sesti F. Do
all voltage-gated potassium channels use MiRPs? Circ Res. 2001 May
25;88(10):981-3.
Bockenhauer D, Zilberberg N, Goldstein SA. KCNK2:
reversible conversion of a hippocampal potassium leak into a voltage-dependent
channel. Nat Neurosci. 2001 May;4(5):486-91.
steve.goldstein@yale.edu
Goldstein
Lab Homepage
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