Groundbreaking Yale Research on Brain Receptors Could Yield Better Treatments for Schizophrenia and Parkinson's

Yale research on the new protein Calcyon could lead to development of more effective drugs for conditions which are marked by dopamine deficiency, such as Parkinson’s, chronic schizophrenia and possibly attention deficit hyperactivity disorder.

Researchers at Yale and Medical College of Georgia have identified proteins in the dopamine signaling pathway, which interact with the D1 receptor, one of five known dopamine receptors. Published in the March 3 issue of Science, the paper describes how a novel protein called Calcyon (for calcium “on”) interacts with the D1 receptor to enhance release of calcium within the cell, thereby increasing dopamine’s actions.

“The D1 receptor is prominent in prefrontal cortical neurons that carry out memory functions and we found that Calcyon is also present in the same cells,” said Patricia Goldman-Rakic, professor of neurobiology, neurology and psychiatry at Yale School of Medicine. “The next step is to learn if Calcyon can increase the response of these neurons in the living animal.”

This work, Goldman-Rakic said, reveals a new pathway for D1 signaling and it opens up the possibility that Calcyon may be a new target for drug development aimed at improving the signaling in cells which are otherwise desensitized to dopamine. This is particularly important because most of the drugs now used in those disorders have negative consequences after long term use.

The team’s studies have now shown that memory impairments produced by loss of D1 stimulation can be reversed by the application of an experimental drug which stimulates the D1 receptor specifically.

“We’ve seen only positive results in laboratory trials,” Goldman-Rakic said. “The time is right for clinical trials with drugs containing D1 agonist properties.”

The research is the result of a long-term collaboration between Yale investigators and Clare Bergson and Robert Levenson, under the sponsorship of the Center for Neuroscience of Mental Disorders directed by Goldman-Rakic. Bergson and Levenson, formerly at Yale, are now in the department of pharmacology and toxicology at the Medical College of Georgia, and at the Pennsylvania State College of Medicine, respectively.

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