Neurochemicals are known to play an important role in regulating many responses of the brain. Now MIT researchers have uncovered new actions related to these chemicals.
"These results underscore the importance of determining whether, as in the C. elegans
nervous system, a diversity of biogenic amine-gated chloride channels function in the human brain," said H. Robert Horvitz of the McGovern Institute for Brain Research at MIT and senior author of the study. "If so, such channels might define novel therapeutic targets for neuropsychiatric disorders, such as depression and schizophrenia."
In 2000, Horvitz's group discovered that serotonin activates a chloride channel they called MOD-1, which inhibits neuronal activity in C. elegans
In the current study, Niels Ringstad and Namiko Abe, a postdoctoral researcher and an undergraduate in Horvitz's laboratory, respectively, looked for other ion channels that could be receptors for biogenic amines. Using both in vitro and in vivo methods, they surveyed the functions of 26 ion channels similar to MOD-1 and found three additional ion channels with an affinity for biogenic amines: dopamine activates one, serotonin another, and tyramine (the role of which in the human brain is unknown) a third. All three were chloride channels, like MOD-1.
"We now have four members of a family of chloride channels that can act as receptors for biogenic amines in the worm," Ringstad said. "That these neurochemicals activate both GPCRs and ion channels means that they can have very complex actions in the nervous system, both as slow-acting neuromodulators and as fast-acting inhibitory neurotransmitters."
It is unknown as yet whether an equivalent to this new class of worm receptor exists in the human brain, but Horvitz points out that worms have proved remarkably informative for providing insights into human biology. In 2002, Horvitz shared the Nobel Prize in Physiology or Medicine for the discovery based on studies of C. elegans
of the mechanism of programmed cell death, a central feature of some neurodegenerative diseases and many other disorders in humans.
"Historically, studies of C. elegans
have delineated mechanisms of neurotransmission that subsequently proved to be conserved in humans," says Horvitz, the David H. Koch Professor of Biology at MIT and a Howard Hughes Medical Institute Investigator. "The next step is to look for chloride channels controlled by biogenic amines in mammalian neurons."