An Intriguing Combination in the Brain May Modify Our Appetites, Alter Other Key Processes

The interaction between a disparate pair of brain proteins may have a profound effect on the regulation of appetite, according to a new study by scientists from the Florida campus of The Scripps Research Institute. The complex partnership may also have an impact on other signaling pathways linked to neuropsychiatric disorders as wide-ranging as Parkinson's disease, schizophrenia, and addiction.

“Our findings provide new insights into the way the body regulates appetite and other processes,” said Roy G. Smith, chair of the Scripps Research Department of Metabolism and Aging, who authored the new study with Staff Scientist Andras Kern and other Scripps Research colleagues. “The work provides exciting opportunities for designing next generation therapeutics with fewer side effects for both obesity and psychiatric disorders associated with abnormal dopamine signaling.”

The study, published in the most recent issue of the journal Neuron, reveals a fascinating partnership within the brain neurons that regulate appetite, a unique complex of hormone and neurotransmitter receptors that no one suspected existed before the new research. 

One of these is the receptor for ghrelin (GHSR1a), a small peptide hormone that is produced mainly in the stomach. As an evolutionary warning signal that promotes weight gain and fat during periods of weight loss, ghrelin can be blamed for the failure of most modern diets.

The other key player is the dopamine receptor known as subtype-2 (DRD2), part of the dopamine signaling pathway. Dopamine is a neurotransmitter that plays a key role in the brain's reward centers, and can lead to pleasure producing behavior, such as drug abuse and overeating.

The study identifies this twin receptor complex, which is naturally present in the brain’s neurons that regulate appetite, and sheds light on its role in modifying dopamine signaling.

“We were able to show there are subsets of brain neurons that express both the ghrelin receptor and the dopamine receptor subtype-2,” Smith said.

The study went on to show that when these two receptors are co-expressed, the receptors physically interact with each other, which leads to an alteration of dopamine signaling. And when mice were treated with a molecule (cabergoline) that selectively activates the dopamine receptor, they lost weight. Interestingly, cabergoline-stimulated weight loss did not require ghrelin, but was dependent on the receptor for ghrelin and its interaction with the dopamine receptor.

In addition, cabergoline blocked dopamine signaling only for the complex—a fact that Smith finds promising. “This allows for neuronal selective fine-tuning of dopamine signaling because neurons expressing only the dopamine receptor will be unaffected,” he said.

In addition to Smith and Kern, authors of the paper, “Apo-Ghrelin Receptor forms Heteromers with DRD2 in Hypothalamic Neurons and is Essential for Anorexigenic Effects of DRD2 Agonism,” are Rosie Albarran-Zeckler and Heidi E. Walsh of Scripps Research. For more information, see http://www.cell.com/neuron/fulltext/S0896-6273(11)01087-7

The study was supported by The National Institutes of Health. 

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