BINDING SITE STRUCTURE OF NEURONAL NICOTINIC RECEPTORS

  • Luetje, Charles W, (PI)

Project: Research project

Description

Neuronal nicotinic acetylcholine receptors (nAChRs) are of great interest
because they are critical sites at which acetylcholine must act to excite
the forebrain. These receptors are of particular interest because they are
the sites at which nicotine exerts its psychoactive and addictive effects.
Pharmacologic intervention at neuronal nAChRs holds promise for treating
the effects of diseases of the central nervous system and for
understanding and treating addictive processes. A particularly important
therapeutic target is the site at which nAChRs bind acetylcholine.
Unfortunately, our understanding of the structural basis for this
interaction is limited. Also, for therapeutic agents to be effective, they
must be capable of distinguishing among the multiple functional subtypes
of nAChRs that are present in the nervous system. The research project
that I describe in this application will identify the specific amino acid
residues that determine the pharmacological properties of the
neurotransmitter binding sites of neuronal nAChRs. The experimental
strategy is to use the pharmacological differences between members of this
receptor family as probes of receptor structure. This will be done using
the techniques of molecular biology. Chimeric receptor subunits will be
constructed by replacing specific sequence segments of one subunit with
the analogous sequence segment of a pharmacologically distinct subunit.
By determining the pharmacological properties of receptors formed by
chimeric subunits, the sequence segments that determine pharmacological
specificity will be identified. Drawing on the results of these
experiments, individual amino acid changes will be made between
pharmacologically distinct receptors. These experiments will identify the
specific amino acids that determine pharmacological specificity. The
results of these experiments will aid in the design of therapeutic agents
selective for individual receptor subtypes. Specific drugs will be of
great use in treating, as well as probing the mechanism of, nicotine
addiction.
StatusFinished
Effective start/end date3/1/945/31/05

Funding

  • National Institutes of Health: $258,012.00
  • National Institutes of Health: $164,306.00
  • National Institutes of Health
  • National Institutes of Health: $44,952.00
  • National Institutes of Health
  • National Institutes of Health: $233,864.00
  • National Institutes of Health: $334,796.00
  • National Institutes of Health
  • National Institutes of Health: $325,306.00
  • National Institutes of Health: $250,497.00

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Nicotinic Receptors
Binding Sites
Pharmacology
Amino Acids
Ligands
Nicotine
Central Nervous System Diseases
Acetylcholine
Neurotransmitter Agents
Anti-Anxiety Agents
Nervous System Diseases
Molecular Structure
Parkinson Disease
Analgesics
Amino Acid Sequence
Schizophrenia
Alzheimer Disease
Prosencephalon
Nervous System
Molecular Biology

ASJC

  • Medicine(all)