Complexin function varies with species

HOUSTON -- (November 16, 2009) -- Complexins are small proteins that regulate the release of neurotransmitters and hormones from neurons, a fundamental function of the brain. Whether complexins helped or hindered this release was unclear until a new study by Baylor College of Medicine researchers demonstrated that they can do both, depending on the species in which they act.

"The balance between these two opposing forces is critical for neurotransmitter release, but during evolution, the balance changed. Complexins have a predominantly inhibitory effect in flies and a facilitatory one in mammals," said Dr. Christian Rosenmund, professor of molecular and human genetics and neuroscience at BCM and professor of neurobiology at the Neuroscience Research Center, Charité - Universitätsmedizin Berlin, Germany. The report appears in the current issue of the journal Neuron.

This difference is important because proteins that mediate and modulate neurotransmitter release are normally very similar in function throughout the animal kingdom. Previous genetic studies on complexin in mice, however, led to findings that were the opposite to those with the equivalent kind of studies in fruit flies.

Implications for humans

"This in turn led to very different ideas about how this fundamentally important protein complexin works," said Dr. Mingshan Xue, whose work on this research received the Gruber International Research Award in Neuroscience from the Society for Neuroscience when he was a student at BCM. He is now a postdoctoral fellow at the University of California San Diego.

Resolving this problem has implications for humans as well because complexins are also associated with neurological disorders such as schizophrenia, bipolar disorders and Huntington's disease.

The Rosenmund laboratory teamed with that of Dr. Hugo Bellen, professor of molecular and human genetics and neuroscience at BCM, to resolve this discrepancy by comparing the behavior of complexins in both species. Xue, the lead author of the study and a graduate student in the Rosenmund laboratory at the time, found that when he introduced the fruit fly complexin into mammalian synapses (the point of connection between two nerve cells), the complexin inhibited neurotransmitter release. When he put the mammalian complexin into the fly, that type of complexin stimulated release. (Bellen is also a Howard Hughes Medical Institute investigator.)

He further showed that complexins in general regulate release through different protein modules that can either inhibit or facilitate release. This principle is absolutely conserved in both species.

However, small differences in the individual module between flies and mammals tilt the balance between the inhibitory function and the facilitatory function, causing overall opposite phenotypes (observable charateristics) in flies and mammals. These results essentially resolve this important controversy in the field, and provide important new information on how neurotransmitter release is regulated.

Others who took part in this work include Yong Qi Lin and Hongling Pan from the Bellen laboratory at BCM, Kerstin Reim from the Max Planck Institute of Experimental Medicine in Goettingen Germany, and Hui Deng from the Rosenmund laboratory at BCM.

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

For more information on basic science at Baylor College of Medicine, please go to www.bcm.edu/fromthelab or www.bcm.edu/news.