The role of proline residues in the structure and function of human MT2 melatonin receptor

Mazna, Petr; Grycová, Lenka; Balík, Aleš; Zemková, Hana; Friedlova, Eliska; Obšilová, Veronika; Obšil, Tomáš; Teisinger, Jan

doi:10.1111/j.1600-079x.2008.00598.x

Cited by 22 publications

(23 citation statements)

References 61 publications

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“…Further insights into structural and functional properties of MT1 and MT2 receptors have been recently provided in a series of molecular modeling studies by Mazna et al . (17), by Rivara et al . (18), and by the groups of Efremov (19) and Chavatte (20), which tentatively described the characteristics of melatonin docking and receptor activation dynamics to identify new selective antagonists.…”

Section: Melatonin Receptorsmentioning

confidence: 95%

Melatonin signaling and cell protection function

et al. 2010

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Besides its well-known regulatory role on circadian rhythm, the pineal gland hormone melatonin has other biological functions and a distinct metabolism in various cell types and peripheral tissues. In different tissues and organs, melatonin has been described to act as a paracrine and also as an intracrine and autocrine agent with overall homeostatic functions and pleiotropic effects that include cell protection and prosurvival factor. These latter effects, documented in a number of in vitro and in vivo studies, are sustained through both receptor-dependent and -independent mechanisms that control detoxification and stress response genes, thus conferring protection against a number of xenobiotics and endobiotics produced by acute and chronic noxious stimuli. Redox-sensitive components are included in the cell protection signaling of melatonin and in the resulting transcriptional response that involves the control of NF-κB, AP-1, and Nrf2. By these pathways, melatonin stimulates the expression of antioxidant and detoxification genes, acting in turn as a glutathione system enhancer. A further and converging mechanism of cell protection by this indoleamine described in different models seems to lie in the control of damage and signaling function of mitochondria that involves decreased production of reactive oxygen species and activation of the antiapoptotic and redox-sensitive element Bcl2. Recent evidence suggests that upstream components in this mitochondrial route include the calmodulin pathway with its central role in melatonin signaling and the survival-promoting component of MAPKs, ERK1/2. In this review article, we will discuss these and other molecular aspects of melatonin signaling relevant to cell protection and survival mechanisms.

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Section: Melatonin Receptorsmentioning

confidence: 95%

Melatonin signaling and cell protection function

et al. 2010

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“…(6) A wealth of conventional mutagenesis studies has already established that these prolines play some significant functional role in GPCRs. (7–14) Proline kinks have long been hypothesized to mediate the helical movements involved in GPCR activation, acting as pivot points, hinges, and/or swivels to expose a G protein binding site at the intracellular end of the helical bundle. (15, 16) A recent crystal structure of the closely related D3 dopamine receptor confirms that the prolines investigated here are associated with helical kinks, especially prominent in TMs 2, 6, and 7 (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Functions of Conserved Prolines within Transmembrane Helices of the D2 Dopamine Receptor

2011

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G protein–coupled receptors (GPCRs) contain a number of conserved proline residues in their transmembrane helices, and it is generally assumed these play important functional and/or structural roles. Here we use unnatural amino acid mutagenesis, employing α–hydroxy acids and proline analogs, to examine the functional roles of five proline residues in the transmembrane helices of the D2 dopamine receptor. The well–known tendency of proline to disrupt helical structure is important at all sites, while we find no evidence for a functional role for backbone amide cis–trans isomerization, another feature associated with proline. At most proline sites, the loss of the backbone NH is sufficient to explain the role of the proline. However, at one site – P2105.50 – a substituent on the backbone N appears to be essential for proper function. Interestingly, the pattern in functional consequences that we see is mirrored in the pattern of structural distortions seen in recent GPCR crystal structures.

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“…Again, there is precedent with several receptors that modification of this important motif can compromise ligand induced activity and/or receptor expression (Wess et al, 1993;Galés et al, 2000;Mazna et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Two Naturally Occurring Mutations in the Type 1 Melanin-Concentrating Hormone Receptor Abolish Agonist-Induced Signaling

Goldstein¹,

Schroeder²,

Fortin³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

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The melanin-concentrating hormone (MCH) receptor type 1 (MCHR1) is a seven-transmembrane domain protein that modulates orexigenic activity of MCH, the corresponding endogenous peptide agonist. MCH antagonists are being explored as a potential treatment for obesity. In the current study, we examined the pharmacological impact of 11 naturally occurring mutations in the human MCHR1. Wild-type and mutant receptors were transiently expressed in human embryonic kidney 293 cells. MCHR1-mediated, G␣ i -dependent signaling was monitored by using luciferase reporter gene assays. Two mutants, R210H and P377S, failed to respond to MCH. Five other variants showed significant alterations in MCH efficacy, ranging from 44 to 142% of the wild-type value. At each of the MCH-responsive mutants, agonist potency and inhibition by (S)-methyl 3-((3-(4-(3-acetamidophenyl) piperidin-1-yl)propyl)carbamoyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (SNAP-7941), an established MCHR1 small-molecule antagonist, were similar to wild type. To explore the basis for inactivity of the R210H and P377S mutants, we examined expression levels of these receptors. Assessment by enzyme-linked immunosorbent assay revealed that cell surface expression of both nonfunctional receptors was comparable with wild type. Overnight treatment with SNAP-7941, followed by washout of antagonist, enhanced MCH induced signaling by the wild-type receptor and restored MCH responsiveness of the P377S but not the R210H variant. It is of note that the two loss-of-function mutants were identified in markedly underweight individuals, raising the possibility that a lean phenotype may be linked to deficient MCHR1 signaling. Formal association studies with larger cohorts are needed to explore the extent to which signaling-deficient MCHR1 variants influence the maintenance of body weight.

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The role of proline residues in the structure and function of human MT2 melatonin receptor

Cited by 22 publications

References 61 publications

Melatonin signaling and cell protection function

Melatonin signaling and cell protection function

Dissecting the Functions of Conserved Prolines within Transmembrane Helices of the D2 Dopamine Receptor

Two Naturally Occurring Mutations in the Type 1 Melanin-Concentrating Hormone Receptor Abolish Agonist-Induced Signaling

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