A high-affinity cocaine binding site associated with the brain acid soluble protein 1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 16; p. e2200545119
• Main Authors: Harraz, Maged M, Malla, Adarsha P, Semenza, Evan R, Shishikura, Maria, Singh, Manisha, Hwang, Yun, Kang, In Guk, Song, Young Jun, Snowman, Adele M, Cortés, Pedro, Karuppagounder, Senthilkumar S, Dawson, Ted M, Dawson, Valina L, Snyder, Solomon H
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.04.2022
• Subjects: Affinity; Animals; Binding Sites; Biological Sciences; Brain; Calmodulin-Binding Proteins - genetics; Calmodulin-Binding Proteins - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caudate-putamen; Cocaine; Cocaine - metabolism; Cocaine - pharmacology; Corpus Striatum - metabolism; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Dopamine; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors; Dopamine transporter; Gene Knock-In Techniques; Humans; Mice; Neostriatum; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nucleus accumbens; Proteins; Rats; Receptors; Receptors, Drug - genetics; Receptors, Drug - metabolism; Synaptosomes; drug abuse; receptor; behavior; BASP1; cocaine
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2200545119

Cocaine exerts its stimulant effect by inhibiting dopamine (DA) reuptake, leading to increased dopamine signaling. This action is thought to reflect the binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share cocaine’s behavioral actions. Further, recent reports show more potent actions of the drug, implying the existence of a high-affinity receptor for cocaine. We now report high-affinity binding of cocaine associated with the brain acid soluble protein 1 (BASP1) with a dissociation constant (Kd) of 7 nM. Knocking down BASP1 in the striatum inhibits [3H]cocaine binding to striatal synaptosomes. Depleting BASP1 in the nucleus accumbens but not the dorsal striatum diminishes locomotor stimulation in mice. Our findings imply that BASP1 is a pharmacologically relevant receptor for cocaine.