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Three amino acids in the D2 dopamine receptor regulate selective ligand function and affinity.

ABSTRACT: The D(2) dopamine receptor is an important therapeutic target for the treatment of psychotic, agitated, and abnormal behavioral states. To better understand the specific interactions of subtype-selective ligands with dopamine receptor subtypes, seven ligands with high selectivity (>120-fold) for the D(4) subtype of dopamine receptor were tested on wild-type and mutant D(2) receptors. Five of the selective ligands were observed to have 21-fold to 293-fold increases in D(2) receptor affinity when three non-conserved amino acids in TM2 and TM3 were mutated to the corresponding D(4) amino acids. The two ligands with the greatest improvement in affinity for the D(2) mutant receptor [i.e., 3-{[4-(4-iodophenyl) piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine (L-750,667) and 1-[4-iodobenzyl]-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine (RBI-257)] were investigated in functional assays. Consistent with their higher affinity for the mutant than for the wild-type receptor, concentrations of L-750,667 or RBI-257 that produced large reductions in the potency of quinpirole's functional response in the mutant did not significantly reduce quinpirole's functional response in the wild-type D(2) receptor. In contrast to RBI-257 which is an antagonist at all receptors, L-750,667 is a partial agonist at the wild-type D(2) but an antagonist at both the mutant D(2) and wild-type D(4) receptors. Our study demonstrates for the first time that the TM2/3 microdomain of the D(2) dopamine receptor not only regulates the selective affinity of ligands, but in selected cases can also regulate their function. Utilizing a new docking technique that incorporates receptor backbone flexibility, the three non-conserved amino acids that encompass the TM2/3 microdomain were found to account in large part for the differences in intermolecular steric contacts between the ligands and receptors. Consistent with the experimental data, this model illustrates the interactions between a variety of subtype-selective ligands and the wild-type D(2), mutant D(2), or wild-type D(4) receptors.

SUBMITTER: Cummings DF

PROVIDER: S-EPMC4896224 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Three amino acids in the D2 dopamine receptor regulate selective ligand function and affinity.

Cummings David F DF Ericksen Spencer S SS Schetz John A JA

Journal of neurochemistry 20090416 1

The D(2) dopamine receptor is an important therapeutic target for the treatment of psychotic, agitated, and abnormal behavioral states. To better understand the specific interactions of subtype-selective ligands with dopamine receptor subtypes, seven ligands with high selectivity (>120-fold) for the D(4) subtype of dopamine receptor were tested on wild-type and mutant D(2) receptors. Five of the selective ligands were observed to have 21-fold to 293-fold increases in D(2) receptor affinity when ...[more]

PMID: 19486266

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Project description:Functional selectivity (or biased agonism) is a property exhibited by some G protein-coupled receptor (GPCR) ligands, which results in the modulation of a subset of a receptor's signaling capabilities and more precise control over complex biological processes. The dopamine D2 receptor (D2R) exhibits pleiotropic responses to the biogenic amine dopamine (DA) to mediate complex central nervous system functions through activation of G proteins and β-arrestins. D2R is a prominent therapeutic target for psychological and neurological disorders in which DA biology is dysregulated and targeting D2R with functionally selective drugs could provide a means by which pharmacotherapies could be developed. However, factors that determine GPCR functional selectivity in vivo may be multiple with receptors, ligands and transducers contributing to the process. We have recently described a mutagenesis approach to engineer biased D2R mutants in which G protein-dependent ([Gprot]D2R) and β-arrestin-dependent signaling ([βarr]D2R) were successfully separated (Peterson, et al. PNAS, 2015). Here, permutations of these mutants were used to identify critical determinants of the D2R signaling complex that impart signaling bias in response to the natural or synthetic ligands. Critical residues identified in generating [Gprot]D2R and [βarr]D2R conferred control of partial agonism at G protein and/or β-arrestin activity. Another set of mutations that result in G protein bias was identified that demonstrated that full agonists can impart unique activation patterns, and provided further credence to the concept of ligand texture. Finally, the contributions and interplay between different transducers indicated that G proteins are not aberrantly activated, and that receptor kinase and β-arrestin activities are inextricably linked. These data provide a thorough elucidation of the feasibility and malleability of D2R functional selectivity and point to means by which novel in vivo therapies could be modeled.

Dataset Information

Three amino acids in the D2 dopamine receptor regulate selective ligand function and affinity.

Publications

Three amino acids in the D2 dopamine receptor regulate selective ligand function and affinity.

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