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Proteins involved in nicotine receptor clustering

Institution: University of California, San Diego
Investigator(s): William Conroy, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0058 Award: $307,246
Subject Area: Nicotine Dependence
Award Type: Research Project Awards

Initial Award Abstract
Smoking of tobacco is linked to a variety of serious diseases, ranging from cardiovascular disease to lung cancer. It is now well established that nicotine is the major active chemical in tobacco that accounts for its continued use in the face of these dire consequences. The actions of nicotine are mediated by proteins found on the surface of neurons, called nicotinic receptors. Nicotinic receptors normally respond to the chemical acetylcholine that is released from other neurons. Nicotine, like acetylcholine, activates the receptors, but after continued exposure can lead to inactivation. Nicotinic receptors are found on neurons throughout the brain, spinal cord, and peripheral ganglia. Many recent studies have attempted to define the receptors through which nicotine exerts its effects. Although there has been much effort, progress has been slow, in part because of the discovery of many different types of nicotinic receptors and the many neuronal processes which are controlled or modulated by these receptors.

One type of nicotinic receptor that has generated a lot of recent interest is one that contains the 7 nicotinic receptor. These receptors are one of the most abundant nicotinic receptors in the nervous system, they are activated by low concentrations of nicotine, and are efficient in letting calcium enter the neuron. The fact that these receptors let calcium enter the neuron means that these receptors can influence a number of calcium-dependent processes within the neuron. Thus, these receptors have been implicated in numerous physiological processes in the developing and adult nervous systems. Many of the neurons which express nicotinic receptors position the receptors in discrete locations or clusters on the cell surface. This compartmentalization of the receptors on the neuron allows for precise activation of subsets of receptors, distinct signaling to the interior of the cell, and separate regulatory control of receptor populations. How the receptors are positioned at distinct sites on the neuron is not known.

It is the goal of this project to determine the proteins involved and the mechanisms used in localizing or clustering nicotinic receptors on neurons. The proposed experiments will visualize receptor clusters on neurons using fluorescent probes and light microscopy. The involvement of other proteins in the clustering of the receptors will be tested by disrupting these proteins and monitoring the receptor clusters. In addition, novel clustering proteins will be identified as associated proteins that purify in combination with the receptor. Lastly, the proteins and mechanisms identified in one neuronal system will then be tested in another neuronal system to validate the universality of these phenomena. These results will provide basic information regarding the function and regulation of the receptors which mediate nicotine’s effects. Understanding the receptors involved and the physiological processes affected by nicotine will be useful in designing new treatments for nicotine addiction and in determining the role these receptors play in human behaviors that initiate tobacco use.

Cluster formation of alpha7-containing nicotinic receptors at interneuronal interfaces in cell culture
Periodical: Neuropharmacology Index Medicus:
Authors: Conroy WG, Ogden LF, Berg DK ART
Yr: 2000 Vol: 39 Nbr: Abs: Pg: 2699-2705

Nicotinic alpha7 receptors: synaptic options and doewnstream signaling in neurons
Periodical: Journal of Neurobiology Index Medicus:
Authors: Berg DK, Conroy WG ART
Yr: 2002 Vol: 53 Nbr: Abs: Pg: 512-523

Developmental expression of nicotinic receptors in the chick and human spinal cord.
Periodical: Journal of Comparative Neurology Index Medicus:
Authors: Keiger CJ, Prevette D, Conroy WG, Oppenheim RW ART
Yr: 2003 Vol: 455 Nbr: Abs: Pg: 86-99

PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons.
Periodical: Neuron Index Medicus:
Authors: Conroy WG, Liu Z, Nai Q, Coggan JS, Berg DK ART
Yr: 2003 Vol: 38 Nbr: Abs: Pg: 759-771

PDZ-Domain proteins interact with nicotinic receptors
Periodical: TRDRP Annual Report to the State of California Legislature Index Medicus:
Authors: Conroy WG ABS
Yr: 2002 Vol: Nbr: Abs: Pg:

EphB2 receptors and src kinase co-distribute with alpha7-nicotinic receptors on ciliary ganglion neurons and mediate nicotinic regulation of gene expression.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Liu Z, Conroy WG, Nai Q, Berg DK ABS
Yr: 0 Vol: Nbr: Abs: Pg: