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RESEARCH INTERESTS
Cellular neurobiology; physiology and pharmacology of ligand- and voltage-gated ion channels
Molecular physiology of ion channels in nerve, muscle and synapse
Mechanisms of sensory transduction, including nociception
Neurotoxins as probes to investigate signaling in the nervous system
PUBLICATIONS
I am a cellular neurobiologist interested in the mechanisms by
which information is conveyed in the nervous system. My
research focuses on the molecular physiology of the synapse
with particular emphasis on ion channels and ligand-receptor
interactions.
In collaboration with the laboratory of Prof. B.M. Olivera, we
are examining a variety of neurotoxic peptides (the
Conotoxins) and are identifying and characterizing their ion
channel targets. We've discovered that some of these
peptides block specific ligand-gated ion channels (for
example nicotinic acetylcholine receptors or glutamate
receptors) whereas others block specific voltage-gated ion
channels (for example sodium channels or calcium channels).
We are also using these toxin to probe the topographical
organization of the channels with regard to their function in
synaptic transmission.
Along another vein we are using the various Conotoxins to
investigate changes that ion channels have undergone in the
course of evolution. We consider different species of animals
as mutants of one another and hope to gain unique insights
by comparative examination of the "mutants" offered by
evolution. Thus, substrates for our study are muscle and
nerve tissues from a variety of animal species ranging from
annelids and arthropods to all five classes of jawed
vertebrates. We are also interested in the expression of
different ion channels during ontogeny and differentiation.
By and large, we conduct our studies on isolated tissues and
dissociated-cell cultures. In addition, to gain insights at a
molecular level, we also study ion channels expressed in
Xenopusoocytes that have been injected with mRNA
extracted from these tissues. We employ a variety of
approaches in our investigations including biochemistry,
electrophysiology, immunology, histochemistry, and
molecular biology. The principal tools we employ are
electrophysiological and optical instrumentation used in
conjunction with microcomputers.
We are also developing a novel approach which exploits
fluorescence microscopy to analyze the binding interactions
of ligand with receptor. This approach is more rapid and
frugal than most conventional biochemical assays, and it can
be used to study the interactions of a various molecules,
including nucleic acids as well as proteins. We're presently
using it to examine the binding of neurotoxins with their ion
channel receptors.
Selected Publications
Kulak JM, McIntosh JM., Yoshikami D, Olivera BM (2001) Nicotine-evoked
transmitter release from synaptosomes: functional association of specific
presynaptic acetylcholine receptors and voltage-gated calcium channels. J.
Neurochem. 77 1581-9.
McIntosh JM, Corpuz GO, Layer RT, Garrett JE, Wagstaff JD, Bulaj G, Vyazovkina
A, Yoshikami D, Cruz LJ, Olivera BM. (2000) Isolation and characterization of
a novel conus peptide with apparent antinociceptive activity. J. Biol. Chem.
275(42) 32391-7.
McIntosh, J. M., S. Gardner, S. Luo, J. E. Garrett and D. Yoshikami (2000) Conus
peptides: novel probes for nicotinic acetylcholine receptor structure and function.
Eur J Pharmacol 393(1-3): 205-8.
Olivera, B. M., L. J. Cruz and D. Yoshikami (1999). Effects of Conus peptides on
the behavior of mice. Curr Opin Neurobiol 9(6): 772-7.
Luo S, Nguyen TA, Cartier GE, Olivera BM, Yoshikami D, McIntosh JM. (1999)
Single-residue alteration in α-Conotoxin PnIA switches its nAChR
subtype selectivity. Biochemsitry 38(44): 14542-8.
Jacobsen, R.B., R.G. DelaCruz, J.H. Grose, J.M. McIntosh, D. Yoshikami and
B.M. Olivera (1999) Critical residues influence the affinity and selectivity of a-
conotoxin MI for nicotinic acetylcholine receptors. Biochemistry
38(40): 13310-5.
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