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Contributions of CNRs to nicotinic signaling

Institution: University of California, San Diego
Investigator(s): Martina Blank, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10FT-0235 Award: $70,000
Subject Area: Nicotine Dependence
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Tobacco smoking is the leading preventable cause of death and disease in developed countries. Nicotine has been identified as the main active substance in tobacco. Nicotine exerts its effects in the body by binding to a family of cell surface proteins called nicotinic receptors. These receptors are present on neurons and are activated by a chemical normally found in the body, namely acetylcholine. Both, acetylcholine and nicotinic receptors are present early during development of the nervous system. Early exposure to nicotine, e.g. during pregnancy, has deleterious effects on the developing nervous system. It is not clear what are the cellular events affected by nicotine-exposure. One of the most abundant nicotinic receptors in the nervous system is a class that has a high relative calcium permeability, exhibit inward rectifying properties, and usually desensitize very rapidly. These receptors display multiple functions depending on their location on the cell surface. Most interestingly, they are thought to be involved in mechanisms that regulate the formation of contacts between neurons (synapses) during development and in the maintenance of these contacts in the mature nervous system. The exact developmental role of these receptors is yet to be determined, and little is known about how the receptors come to be positioned at specific sites on a neuron. This directs attention to regulatory proteins controlling nicotinic receptor function and distribution on neurons.

Recently, a new family of proteins has been identified that are located on the surface of neurons and show similarities to the cell adhesion molecule cadherin. These proteins are called cadherin-related neuronal receptors (CNRs) and seem to provide a recognition code for neurons that are supposed to link up. The experiments proposed in this project will test the idea that these proteins can regulate the distribution and function of nicotinic receptors during development of the nervous system. To address this issue, I will make use of a relatively simple neuronal network as a model system for nicotinic synapse formation and modulation. First, I will isolate and characterize these proteins from neuronal tissue, and then examine if they can be found at similar locations than the nicotinic receptors on the neurons. Second, I will try to inactivate these proteins and subsequently analyze the effect of this inactivation on the distribution and function of the nicotinic receptors.

The results arising from this project will provide new information about the mechanisms determining the location of nicotinic receptors on neurons during development and may suggest developmental events at risk by prolonged exposure to nicotine, e.g. during pregnancy. A better understanding of the consequences of smoking on the developing nervous system may suggest intervention strategies of biomedical relevance.

Maturation of postsynaptic nicotinic structures on autonomic neurons require innervation but not cholinergic transmission.
Periodical: European Journal of Neuroscience Index Medicus:
Authors: Kaiser S, Blank M, and Berg DK ART
Yr: 0 Vol: Nbr: Abs: Pg:

Cadherin-related neuronal receptors in nicotinic synapse formation in the chick ciliary ganglion
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Blank M, Berg DK ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Cadherin-related receptors at nicotinic synapses in the chick ciliary ganglion
Periodical: TRDRP Annual Report to the State of California Legislature Index Medicus:
Authors: Blank M, Berg DK ABS
Yr: 2002 Vol: Nbr: Abs: Pg:

Cadherin-related neuronal receptors in chick brain and ciliary ganglia
Periodical: Keystone symposium on the Nuclear Receptor Gene Family Index Medicus:
Authors: Blank M, Berg DK ABS
Yr: 0 Vol: Nbr: Abs: Pg: