Folding Efficiency Is Rate-limiting in Dopamine D4 Receptor Biogenesis

Abstract

Dopamine receptors are G protein-coupled receptors that are critically involved in locomotion, reward, and cognitive processes. The D2 class of dopamine receptors (DRD2, -3, and -4) is the target for antipsychotic medication. DRD4 has been implicated in cognition, and genetic studies have found an association between a highly polymorphic repeat sequence in the human DRD4 coding region and attention deficit hyperactivity disorder. Using DRD4 as a model, we show that antipsychotics can function as potent pharmacological chaperones up-regulating receptor expression and can also rescue a non-functional DRD4 folding mutant. This chaperone-mediated up-regulation involves reduced degradation by the 26 S proteasome; likely via the stabilization of newly synthesized receptor in the endoplasmic reticulum. Dopamine itself can function as a chaperone when shuttled into the cell by means of the dopamine transporter. Furthermore, different repeat variants of DRD4 display differential sensitivity to this chaperone effect. These data suggest that folding efficiency may be rate-limiting for dopamine receptor biogenesis and that this efficiency differs between receptor variants. Consequently, the clinical profile of dopaminergic ligands, including antipsychotics, may include their ability to serve as pharmacological chaperones.

Opioid Receptor Pharmacological Chaperones Act by Binding and Stabilizing Newly Synthesized Receptors in the Endoplasmic Reticulum

“…The inherent conformational flexibility that is needed for the functional activity of GPCRs may thus make these proteins very susceptible for inappropriate ER retention and in some cases may result in slow kinetics of folding and maturation. This may also apply to a few other wild-type GPCRs, like the rat luteinizing hormone and mouse V2 vasopressin receptors and the human D4 dopamine, GnRH, and Pael receptors that have been shown to mature inefficiently (16,23,24,29,56). The slow folding kinetics is probably not entirely disadvantageous, however, and may even allow cells to regulate the level of mature receptors at the plasma membrane.…”

“…Subsequently, a similar strategy has been applied for mutant forms of the gonadotropin-releasing hormone receptor, rhodopsin, and melanin-concentrating hormone receptor 1 (16 -21). Furthermore, since receptor-specific ligands have also been found to be effective in enhancing cell surface targeting of a few wild-type GPCRs (16,(21)(22)(23)(24)(25)(26), pharmacological chaperones may have significance not only in rescuing mutant GPCRs but also in regulating wild-type receptor levels.It has been hypothesized that pharmacological chaperones enhance cell surface targeting of GPCRs by binding and * …”

A neurochemical approach to valuation sensitivity over gains and losses

“…Our research is accomplished independently of two recent neurogenetics studies of financial risk-taking (Dreber et al 2009;Kuhnen & Chiao 2009) using sample sizes of 98 and 65, respectively. They show that subjects with the 7-repeat allele in the dopamine receptor D4 gene (DRD4) exon 3, hence low DA tone (Van Craenenbroeck et al 2005) is more risk-tolerant than subjects without the 7-repeat allele. Both results, being in the same direction as the current report, corroborate our conjecture that DA tone modulates sensitivity of valuation over gains.…”

The molecular genetic architecture of human personality: beyond self-report questionnaires

“…[110][111][112][113] One avenue of future research would be to examine all three loci in a single haplotype for their joint effect on expression. It would be of considerable value to know whether these various polymorphisms additively contribute to expression or is one locus a major determinant in regulating protein receptor levels?…”

“…DRD4 exon III repeat region has functional consequences Studies of G protein coupling, 110 cyclic AMP synthesis, 111 in vitro expression 112 and chaperone-induced folding 113 provide increasingly solid evidence that the shorter exon III repeats code for a more efficient gene at the level both of transcription, translation and second messenger generation compared to the D4.7 repeat.…”