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A peptide targeting an interaction interface disrupts the dopamine D1‐D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism
Author(s) -
Hasbi Ahmed,
Perreault Melissa L.,
Shen Maurice Y. F.,
Zhang Lucia,
To Ryan,
Fan Theresa,
Nguyen Tuan,
Ji Xiaodong,
O'Dowd Brian F.,
George Susan R.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-254037
Subject(s) - dopamine receptor d2 , 5 ht5a receptor , dopamine receptor d1 , receptor , g protein coupled receptor , nuclear receptor co repressor 1 , chemistry , pharmacology , biology , biochemistry , nuclear receptor , gene , transcription factor
Although the dopamine D1‐D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1‐D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1‐D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues 404 Glu and 405 Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1‐D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmunoprecipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G‐protein affinities and loss of calcium signaling, resulting in the inhibition of D1‐D2 heteromer function. The use of the D1‐D2 heteromer‐disrupting peptide in vivo revealed a pathophysiological role for the D1‐D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment.—Hasbi, A., Perreault, M. L., Shen, M. Y. F., Zhang, L., To, R., Fan, T., Nguyen, T., Ji, X., O'Dowd, B. F., George, S. R., A peptide targeting an interaction interface disrupts the dopamine D1‐D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism