December 2, 2009

Genetic ‘Flower’ Cited As Missing Link In Neuronal Information Transfer

The transmission of information from one neuron to the next is an unseen intricate ballet.

Tiny vesicles "“ bubbles containing the chemical neurotransmitters that make information exchange possible"”travel to the tip of neurons (synapses), where they fuse with the cell's membrane in a process called exocytosis.

The extra membrane is then captured in a process called endocytosis and recycled to form a new vesicle to enable the next cycle of release. The two processes, exocytosis and endocytosis, are tightly coupled making rapid neurotransmission with neurons firing impulses 500 times a second a reality, said researchers led by Dr. Hugo Bellen, professor of molecular and human genetics at Baylor College of Medicine. A gene called flower encodes for a critical calcium channel and makes this rapid transmission possible, said Bellen and his colleagues in a report that appeared in a recent issue of the journal Cell.

Calcium influx

The release of the vesicles or bubbles by exocytosis begins with calcium influx into the synapse (the axon-to-dendrite junction between two neurons) through tiny pores or channels in the membrane. In this case the pores or channels are commonly known as calcium channels. Since neurons can fire impulses as frequently as 500 times a second, the calcium that flows into the synapses must be removed very rapidly to keep the process going.

After exocytosis, the vesicle membranes must be retrieved, and this process is also stimulated by an increase in calcium in the synapses. The channel that mediates this influx was unknown until Bellen and his colleagues identified it in an elegant series of experiments.

Interestingly, this channel is present in the vesicles. Hence, the vesicles carry the means to activate their own re-uptake.

A gene called flower

A genetic screen identified a novel gene called flower as coding for this channel. Dr. Chi-Kuang Yao, a postdoctoral fellow in Bellen's laboratory, mapped the gene and showed that the corresponding protein is present in the membrane of synaptic vesicles. He then showed that fruit flies lacking this gene were less able to endocytose vesicles.

Direct experiments involved purifying the Flower protein, putting it into liposomes or artificial vesicles and showing that several copies of the protein can aggregate together and form a channel in membranes. When calcium was introduced into this system, it could enter the vesicle, showing that the protein allows calcium entry.

Vesicle carries its own destruction

"The vesicle carries its own channel to promote endocytosis," said Bellen. "It is a simple regulatory system. The mechanism links exocytosis and endocytosis."

Bellen is director of the BCM program in developmental biology and a Howard Hughes Medical Institute investigator.

Others who took part in this research include Yong Qi Lin, Cindy V. Ly, Tomoko Ohyama, Claire M. Haueter, Vera Y. Moiseenkova-Bell and Theodore G. Wensel, all of BCM.

Funding for this work came from the National Institute of Neurological Diseases and Stroke, the BCM Intellectual and Developmental Disabilities Research Center and the Howard Hughes Medical Institute.


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