Major depression is an illness associated with significant loss of function and quality of life as well as a high mortality rate.  Recently, it has been reported that a coupling or physical interaction between two types of dopamine receptors, termed D1 and D2, is elevated in the brains of patients who have been diagnosed with major depression, in comparison to the normal population (1).  This receptor complex was studied in autopsied brain tissue to determine the specific point of interaction between the two large protein receptors. In an effort to develop a treatment with a unique mechanism of action, researchers used a 15 amino acid peptide that mimics the interface of one of the proteins to interfere with the coupling of the two receptors (2).  That peptide was used as a model in the current study to design even smaller peptides to disrupt the D1-D2 receptor complex. These smaller peptides will then be used to assess the effects of the peptides on the purified receptors themselves, as well as on the receptors in mammalian cell extracts. Several peptides have been synthesized, purified, and analyzed. These peptides are based on the sequence Met-Lys-Ser-Asn-Gly-Ser-Phe-Pro-Val-Asn-Arg-Arg-Arg-Val-Glu, representing Met 257 to Glu 271 of the D2 receptor in the region where it interacts with the D1 receptor, and include the N-terminal sequence, the C-terminal sequence, and two internal sequences of different lengths.  Each peptide was tested to see if it disrupts the receptor complex using immunoprecipitation assays and cross-linking gel electrophoresis assays. Progress may lay the foundation for the development of a new class of pharmaceuticals to treat depression and will further enhance our understanding of one of the underlying mechanisms of this debilitating illness. Fuxe, K., et al. Brain Res Rev. 58 , 415-452 (2008).Pei, L. et al. Nature Medicine 16(12) , 1393-1395 (2010).

Understanding the biochemical basis of depression: Using small peptides to disrupt the D1-D2 dopamine receptor complex

247th National Meeting (2014)

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