title: 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.
abstract: 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.
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; and Department of Pharmacology and.
authors: Ahmed
authors: A
authors: Hasbi
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; and Department of Pharmacology and.
authors: Melissa L
authors: ML
authors: Perreault
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; and Department of Pharmacology and.
authors: Maurice Y F
authors: MY
authors: Shen
authors: Department of Pharmacology and.
authors: Lucia
authors: L
authors: Zhang
authors: Department of Pharmacology and.
authors: Ryan
authors: R
authors: To
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; and Department of Pharmacology and.
authors: Theresa
authors: T
authors: Fan
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; and Department of Pharmacology and.
authors: Tuan
authors: T
authors: Nguyen
authors: Department of Pharmacology and.
authors: Xiaodong
authors: X
authors: Ji
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; and Department of Pharmacology and.
authors: Brian F
authors: BF
authors: O'Dowd
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; and Department of Pharmacology and Department of Medicine, University of Toronto, Toronto, Ontario, Canada s.george@utoronto.ca.
authors: Susan R
authors: SR
authors: George
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D055503:Protein Multimerization; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D010455:Peptides; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D004298:Dopamine
keywords: GPCR oligomerization; behavioral despair; depression; heterooligomer