September 27, 2007
La Jolla, CA – It is all about being at the right place at the right time. We have all learned the lesson that location matters and the same holds true for neurons, maybe even more so.
Researchers at the Salk Institute for Biological Studies have revealed that nicotinic receptors, small molecules found on the surface of nerve cells in the brain and the rest of the nervous system, prefer distinct cellular subdivisions and have identified important key elements that coax them into the right neighborhood.
The Salk research team – led by Stephen F. Heinemann, Ph.D., a professor in the Molecular Neurobiology Laboratory – published their findings in the Sept. 20, 2006 issue of the Journal of Neuroscience.
Nicotinic receptors form ion channels in the plasma membrane of cells and open and close in response to acetylcholine, a chemical messenger in the brain. Nicotinic receptors are present on many neurons and play an important role in many basic physiological processes and in diseases such as Alzheimer’s disease and Parkinson’s’ disease. Nicotine, the addicting substance in tobacco, acts through the same receptor.
“The nicotinic receptors arguably have the longest history of experimental study of any receptors,” said Heinemann. “We were the first to clone these receptors 20 years ago. Despite the realization that functions of these receptors depend critically on their locations in specific regions of the neuron, little is known about the subcellular distribution of nicotinic receptors, and even less is known about the mechanisms responsible for their assembly and targeting process. With this study, we have finally gained valuable information about where and how these brain receptors are expressed. This is of great importance in the understanding of how nicotinic receptors may be involved in normal and/or pathological conditions.”.
Compared to other cells, neurons are highly polarized and compartmentalized. They consist of a cell body containing the nucleus and an electrically excitable output fiber, the axon, while incoming messages are received by dendrites. Within these two major compartments, the axons and dendrites, specialized subzones and structures ensure the “multitasking” capabilities of individual neurons. Meanwhile, the precise location of neuronal proteins is critical for them to properly perform their designated tasks.
“Our research was aimed at determining the precise subcellular locations of nicotinic receptors within neurons, ” explained postdoctoral researcher and first author Jian Xu, Ph.D.
The Salk researchers’ findings demonstrated for the first time that two major types of nicotinic receptors are not distributed equally but follow distinct patterns. “We discovered that different nicotinic receptors prefer different locations in neurons. This observation immediately suggested that the two classes of receptors we studied might each carry out different functions,” explained co-author Yongling Zhu, Ph.D., a postdoctoral researcher in Heinemann’s laboratory.
Once the Salk researchers had determined that the receptors cluster in certain areas of neurons, they decided to find out how the receptors knew where to go. “We started searching for signals that may be recognized and used as tickets to direct the receptors’ traffic route in neurons. Through systematic screening, we identified two novel sequence motifs that are critical for directing nicotinic receptors toward either dendrites or axons. Remarkably, attaching these signals to proteins that usually don’t show any preference for any particular compartment, sent the fusion proteins to either dendrites or axons,” said Xu.
This study also bears important implications for nicotine addiction. “Ultimately, we are trying to understand how smoking may trigger addiction,” added Heinemann. “Knowing where receptors are located will undoubtedly help researchers to uncover the initial reaction sites of nicotine inhaled through cigarette smoking. There is a clear beneficial outcome of our findings in the future therapeutic treatment of nicotine addition.”
Despite increasing bans on smoking in public places, in 2003, more than 70 million people smoked, at least occasionally, making nicotine one of the most widely abused substances in the U.S. Worldwide, 20 percent of the population will die early from smoking, making nicotine addiction a major preventable disease.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.