The structure and function of nicotinic acetylcholine receptors.
The autoimmune response to nicotinic receptors which causes myasthenia
gravis: what initiates it, the pathological mechanisms by which
it impairs neurosmuscular transmission, and how to specifically
suppress it. The mechanisms of the differing effects of nicotine
on the many subtypes of receptor: activation, desensitization,
channel block, increased synthesis, and decreased turnover. The
physiological roles of nicotinic receptors in development of specific
synaptic connections, synaptic plasticity in learning and memory,
and non-neuronal tissues. The pathological roles of nicotinic
receptors in myasthenia, dysautonomia, epilepsy, myopia, Alzheimer's
disease, and addiction to tobacco.
Monoclonal antibodies; affinity chromatography; cloning and expression
of native and mutant cDNAs; electrophysiology, and ligand binding.
We are studying the biochemical and antigenic structure of nicotinic
receptors from human muscle and Torpedo electric organ. We investigate
pathological mechanisms and specific immunosuppressive therapy
of experimental autoimmune myasthenia gravis in rats induced by
immunization with purified receptor.
We are also studying the structure and function of neuronal nicotinic
receptors. These studies primarily involve expression of cloned
human receptors in Xenopus oocytes and permanently transfected
cell lines.
We are also studying the effects of acute and chronic exposure
to nicotine on various subtypes of nicotinic receptors. Understanding
these effects is important for explaining both the effects of
nicotine in tobacco and the effects of nicotinic drugs which are
being developed. These structures should also reveal mechanisms
through which nicotinic receptors could influence development
and synaptic plasticity. Receptors are normally exposed to acetylcholine
for milliseconds, but can be exposed to nicotine for hours. Nicotine,
like any agonist, initially activates and then desensitizes receptors.
On prolonged exposure it increases assembly of receptor subunits
and decreases turnover of receptors in the surface membrane. It
can be a full or partial agonist and block the cation channel.
All of these effects vary depending on the receptor subtype. Combinations
of these effects on various receptor subtypes in various regions
are responsible for addiction to nicotine, tolerance to some of
its effects, and mediating its many effects, which range from
enhanced cognition to reduced anxiety and pain.
KEY WORDS: Acetylcholine receptors; myasthenia gravis;
nicotine.
Gerzanich V., Wang F., Kuryatov A. and Lindstrom J.M. (1998) a5
subunit alters desensitization, pharmacology, Ca++ permeability,
and Ca++ modulation of human neuronal a3
nicotinic receptors. J Pharmacol Exper Ther. 286:311-320. Online PDF File
Wang F., Nelson M., Kuryatov A., Olale F., Cooper J., Keyser K. and Lindstrom J.M. (1998) Chronic nicotine treatment upregulates human a3b2, but not a3b4 AChRs stably transfected in human embryonic kidney cells. J Biol Chem. 273(44):28721-28732. Online PDF File
Nelson M. and Lindstrom J.M. (1999) Single channel properties of human AChRs: impact of and subunits. J Physiol. 516(3):657-678. Online PDF File
Lindstrom J.M. (2000) The structure of neuronal nicotinic receptors.
In Neuronal Nicotinic Receptors. Eds. F. Clementi, C. Gotti, D.
Fornasari, Springer, New York, Handbook of Experimental Pharmacology.
Vol. 144 pp. 101-162.
Lindstrom J.M. (2000) Acetylcholine receptors and myasthenia.
Muscle and Nerve. 23(4):453-477. Online PDF File
Kuryatov A., Olale F., Choi C. and Lindstrom J.M. (2000) AChR
extracellular domain determines sensitivity to nicotine-induced
inactivation. Eur J Pharmacol. 393:11-21. Online PDF File
Kuryatov A., Olale F., Cooper J., Choi C. and Lindstrom J.M.
(2000) Human a6 AChR
subtypes: subunit composition, assembly, and pharmacological responses.
Neuropharmacology. 39(13):2570-2590. Online PDF File
Nelson M., Wang F., Kuryatov A., Choi C. Gerzanich V., and Lindstrom
JM. (2001) Functional properties of human nicotinic AChRs expressed
by IMR-32 neuroblastoma cells resemble those of a3b4
AChRs expressed in permanently transfected HEK cells. J Gen Physiol.
118(5): 563-582. Online PDF File
Shelton G.D., and Lindstrom J.M. (2001) Spontaneous remission
in canine myasthenia gravis: implications for assessing human
MG therapies. Neurology. 57(11):2139-2141. Online PDF File
Lindstrom J.M. (2002) Acetylcholine receptor structure. Myasthenia
Gravis and Related Disorders, ed. H. Kaminsky, Humana Press, Inc.,
Totowa NJ. pp. 15-53.
Rush, R., Kuryatov, A., Nelson, M.E. and Lindstrom, J.M. (2002)
First and second transmembrane segments of a3,
a4, b2,
and b4 AChR subunits
influence the efficacy and potency of nicotine. Mol. Pharmacol.
61(6):1416-1422. Online PDF File
Lindstrom, J.M. (2002) Autoimmune diseases involving nicotinic
receptors. J. Neurobio. 53(4):656-665. Online PDF File
Nelson, M.E., Kuryatov, A., Choi, C.H., Zhou, Y., and Lindstrom,
J.M. (2003) Alternate stoichiometries of a4b2
nicotinic acetylcholine receptors. Mol. Pharmacol. 63:332-341.
Online PDF File
Zhou, Y., Nelson, M.E., Kuryatov, A., Choi, C., Cooper, J., and
Lindstrom, J.M. (2003) Human a4b2
AChRs formed from linked subunits. J Neurosci. 23(27):9004-9015.
Online PDF File
Obaid, A.L., Nelson, M.E., Lindstrom, J., and Salzberg, B.M.,Optical studies of nicotinic acetylcholine receptor subtypes in the guinea-pig enteric nervous sytem, J Experi Biol 208:2981-3001, 2005.
