Researchers at the University of Toronto, the Centre for Addiction and Mental Health (CAMH) and the Hospital for Sick Children (HSC) have discovered a cellular communication method in the brain that could lead to improved treatments for schizophrenia and addiction.
Many of the symptoms associated with schizophrenia and addiction are caused by either too much or too little dopamine and GABA, chemicals in the brain that help regulate learning, memory, emotion and cognition. In a study published in the Jan. 20 edition of the journal Nature, researchers demonstrate how proteins can modify each other's function - including the ability of neurons to accept or reject dopamine and other neurochemicals - by binding to each other.
"What we found is a previously unknown method of signal transduction between two structurally different neurotransmitter receptor systems, that is, the direct physical coupling of these proteins," says senior author Dr. Hyman Niznik, associate professor of psychiatry and pharmacology at U of T and section head, laboratory and molecular neurobiology at CAMH. "This may provide us with a new therapeutic window on how to restore normal cellular function in diseases like schizophrenia with the right medication that can either block this interaction or make it happen."
Brain cells communicate with each other via neurotransmitters - natural chemicals that interact with proteins, or receptors, on adjacent neurons. There are many different types of receptors in the brain, some of which respond only to dopamine and some only to the neurotransmitter GABA [g-aminobutyric acid]. Of the many dopamine receptors, two - D1 and D5 - are very similar and respond to the same drugs. Many of the negative symptoms of schizophrenia and addiction are regulated by D1-like receptors.
Niznik and his team of researchers demonstrated that dopamine D5 receptors can directly modify the function of GABA receptors by directly binding to them and forming a receptor-receptor complex. "GABA receptors are structurally different from dopamine D5 receptors, and act as the major shutdown systems for virtually every part of the brain," says co-author Dr. Yu Wang, associate professor of laboratory medicine and pathobiology at U of T and scientist at HSC's research institute. Dopamine receptors were previously believed to be able to modify GABA receptors only by interacting with another protein, called G-proteins.
"We've shown how these two receptor proteins bind to each other in order to modify each other's function," Niznik says. "It's like cutting out the middle guy - you don't need the G-protein to let these receptors "talk" to each other. We believe this to be a very general phenomenon." Niznik expects to find many other pairs of brain cell surface receptors that physically couple to each other to regulate brain function.
The researchers believe this study also provides some answers as to why there are many different types of receptors - like D1 and D5 - that until now appeared to carry out the same function. "The same protein that turns cells on in one part of the brain can have little or no effect on another part, depending on which receptor it physically couples to," he says.
"Our next step will be to demonstrate that there is a malfunction in this coupling phenomenon between these neurotransmitter receptor proteins in the brains of schizophrenics," says lead author Dr. Fang Liu, research scientist at CAMH. The researchers believe this work will ultimately introduce a whole new field of study in signal transduction and molecular neuropsychiatry.
This study was funded by the Medical Research Council, the Ontario Mental Health Foundation, the Canadian Psychiatric Research Foundation, the National Institute of Drug Abuse and the C. Cleghorn Fellowship in Schizophrenia Research at U of T and CAMH.
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