The APCs of nerve cell function

Rapid information processing in the nervous system requires synapses, specialized contact sites between nerve cells and their targets. One particular synapse type, cholinergic, uses the chemical transmitter acetylcholine to communicate between nerve cells. Cholinergic synapses are essential for normal learning and memory, arousal, attention, and all autonomic (involuntary) nervous system functions. Malfunction of cholinergic synapses is implicated in Alzheimer's disease, age-related hearing loss, autonomic neuropathies, and certain forms of epilepsy and schizophrenia. Despite the importance of cholinergic synapses for cognitive and autonomic functions, little is known about the mechanisms that direct their assembly during development.

In a new study published in the June 2008 issue of Molecular and Cellular Neuroscience, researchers at Tufts University School of Medicine (TUSM), uncover mechanisms that direct cholinergic synapse assembly between neurons in vivo.

"We have identified the protein adenomatous polyposis coli (APC) as a key organizer of a multi-protein complex that is required for assembly of neuronal cholinergic synapses" says corresponding author Michele H. Jacob, PhD, professor of neuroscience at TUSM and member of the neuroscience program faculty of the Sackler School of Graduate Biomedical Sciences.

"APC is expressed in all cell types and has multiple functions and binding partners. It is best known for its role in colorectal cancer. Our work defines a novel role for APC in neurons. We show that APC brings together several proteins at the synapse and coordinates their functions in directing the surface membrane delivery and stable retention of nicotinic acetylcholine receptors at the synapse."

"A single nerve cell synthesizes multiple different neurotransmitter receptor types. The nerve cell must target each of them to distinct synaptic sites that oppose incoming nerve cell contacts that release the correct transmitter to activate that receptor type. Matching of receptor and transmitter types is critical for proper function," states Madelaine Rosenberg, PhD, first author and research associate in the department of neuroscience at TUSM.

Rosenberg says that APC and its associated proteins play a key role in accomplishing this task at cholinergic synapses. The authors report that APC interacts with and positions the microtubule plus-end binding protein EB1 and thereby directs the delivery of acetylcholine receptors to restricted surface membrane regions. APC and EB1 interact with other proteins, cytoskeletal regulators and adapter proteins, which together stabilize the scaffold at the synapse and link acetylcholine receptors to APC at the complex. This study identifies several novel components of neuronal nicotinic cholinergic synapses.

Jacob and colleagues showed that blocking APC function led to dramatic and specific decreases in acetylcholine receptor levels at synapses. They showed this by using molecular techniques to manipulate APC protein interactions during synapse formation. "We study an in vivo model system to gain insights into mechanisms that likely direct synapse assembly and function in the human nervous system," Jacob explains. She further suggests that their data "support the emerging concept that APC is a central organizer of a core multi-protein complex that directs the assembly of excitatory, but not inhibitory, synapses in the vertebrate nervous system.

The importance of APC's neural role is highlighted by reports that loss of function gene mutations correlate with mental retardation, schizophrenia, and autism spectrum disorders." Jacob notes, "By identifying the synapse organizing role of APC and its associated proteins, our findings bring us closer to understanding disorders of cognition and neurological function on a molecular level."

Source: Tufts University

Related stories:

A new cellular pathway linked to cancer is identified
In the life of a cell, the response to DNA damage determines whether the cell is fated to pause and repair itself, commit suicide, or grow uncontrollably, a route leading to cancer. In a new study, published in the July 25th issue of Cell, scientists at NYU Langone Medical Center have identified a way that cells respond to DNA damage through a process that targets proteins for disposal. The finding points to a new pathway for the development of cancer and suggests a new way of sensitizing cancer cells to treatment.
Death, division or cancer? Newly discovered checkpoint process holds the line in cell division
Each day, a staggering number of cells perform a feat that still amazes researchers with its complexity: they divide to produce perfect replicas of each other. The process is called mitosis, and an inability to control it is one of the hallmarks of cancer.
Vitamin D and calcium influence cell death in the colon, researchers find
Researchers at Emory University are learning how vitamins and minerals in the diet can stimulate or prevent the appearance of colon cancer. Emory investigators will present their findings on biological markers that could influence colon cancer risk in three abstracts at the American Association for Cancer Research meeting in San Diego.
Stem cells and cancer: cancer pathways that also control the adult stem cell population
Speaking today (10 April) at the UK National Stem Cell Network Annual Science Meeting in Edinburgh, Professor Alan Clarke from Cardiff University describes his work to investigate a mechanism that normally drives adult stem cells to repair the intestine.
Key found to breakthrough drug for clot victims
A team of researchers at Oregon Health & Science University and Washington University in St. Louis have described for the first time the mechanism that gives a mutant enzyme molecule that they have engineered – and patented – the potential to become a breakthrough drug for treating heart attacks and strokes.
New function for colon cancer gene found
Dartmouth Medical School geneticists have discovered a striking turnabout role for a gatekeeper known to put on the brakes for colon cancer. Flaws in a gene called adenomatous polyposis coli (APC), which normally prevents excessive cell growth, are thought to trigger development of most colorectal cancers.
Green Grid Plans First Technical Summit
The new consortium is expected to produce detailed technical objectives and launch programs in an effort to help the IT industry cut back on electrical power.
Scientists identify a gene that may suppress colorectal cancer
In today’s online edition of Genome Research, a husband-and-wife research team from Thomas Jefferson University report the discovery of a gene that, when mutated, may suppress colorectal cancer. To conduct the study, the researchers used a strain of mice that develop polyps, or small growths of tissue, in the digestive tract—the harbingers of cancer. When these mice possessed one copy of the mutated gene, the incidence of small intestinal and colon polyps were reduced by about 90%.

News discussion:

Medicine & Health news