Palmitoylation stabilizes unliganded rod opsin

Maeda, Akiko; Okano, Kiichiro; Park, Paul Shin-Hyun; Lem, Janis; Crouch, Rosalie K.; Maeda, Tadao; Palczewski, Krzysztof

doi:10.1073/pnas.1000640107

Cited by 46 publications

(44 citation statements)

References 33 publications

(31 reference statements)

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“…For example, a recent report describes the photoreceptor cell degeneration of mice expressing a palmitoylation-null rhodopsin, but only when the mice were exposed to bright light. Under normal laboratory lighting conditions, no defect was noted (53). It is possible that ␤ 1 AR mutated at the proximal site would similarly have a dramatic defect in experiments testing stress conditions over a long term experiment in animal models.…”

Section: Discussion ␤ 1 Ar Is S-palmitoylated At Two Sites In Its Cytmentioning

confidence: 99%

Differential Regulation of Two Palmitoylation Sites in the Cytoplasmic Tail of the β1-Adrenergic Receptor

Zuckerman

Hicks

Charron

et al. 2011

Journal of Biological Chemistry

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S-Palmitoylation of G protein-coupled receptors (GPCRs) is a prevalent modification, contributing to the regulation of receptor function. Despite its importance, the palmitoylation status of the ␤ 1 -adrenergic receptor, a GPCR critical for heart function, has never been determined. We report here that the ␤ 1 -adrenergic receptor is palmitoylated on three cysteine residues at two sites in the C-terminal tail. One site (proximal) is adjacent to the seventh transmembrane domain and is a consensus site for GPCRs, and the other (distal) is downstream. These sites are modified in different cellular compartments, and the distal palmitoylation site contributes to efficient internalization of the receptor following agonist stimulation. Using a bioorthogonal palmitate reporter to quantify palmitoylation accurately, we found that the rates of palmitate turnover at each site are dramatically different. Although palmitoylation at the proximal site is remarkably stable, palmitoylation at the distal site is rapidly turned over. This is the first report documenting differential dynamics of palmitoylation sites in a GPCR. Our results have important implications for function and regulation of the clinically important ␤ 1 -adrenergic receptor.

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Section: Discussion ␤ 1 Ar Is S-palmitoylated At Two Sites In Its Cytmentioning

confidence: 99%

Differential Regulation of Two Palmitoylation Sites in the Cytoplasmic Tail of the β1-Adrenergic Receptor

Zuckerman

Hicks

Charron

et al. 2011

Journal of Biological Chemistry

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“…Both ultra-high-resolution SD-OCT (Bioptigen) and SLO (HRAII; Heidelberg Engineering) were used for in vivo imaging of mouse retinas as previously described (11).…”

Section: Methodsmentioning

confidence: 99%

“…Fundus autofluorescence levels did not correlate with amounts of age-related retinoid byproducts, such as N-retinyl-N-retinylidene-ethanolamine (A2E), in the eyes of these mice (Supplemental Figure 1B). These spots could, however, indicate immune cell activation and infiltration into the subretinal space (11). In vivo spectral domain-optical coherence tomography (SD-OCT) and plastic block sections indicated possible infiltrative cells in 8-month-old A/J mice, but not B6 mice ( Figure 2B).…”

Section: Figurementioning

confidence: 99%

Inflammatory priming predisposes mice to age-related retinal degeneration

Mustafi¹,

Maeda²,

Kohno³

et al. 2012

J. Clin. Invest.

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Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age-related disorders, but their complex etiology is poorly understood. Postmitotic neurons, such as photoreceptor cells in the retina and epithelial cells in the adjacent retinal pigmented epithelium, are especially susceptible to cellular senescence, which contributes to age-related retinal degeneration (ARD). The multigenic and complex etiology of ARD in humans is reflected by the relative paucity of effective compounds for its early prevention and treatment. To understand the genetic differences that drive ARD pathogenesis, we studied A/J mice, which develop ARD more pronounced than that in other inbred mouse models. Although our investigation of consomic strains failed to identify a chromosome associated with the observed retinal deterioration, pathway analysis of RNA-Seq data from young mice prior to retinal pathological changes revealed that increased vulnerability to ARD in A/J mice was due to initially high levels of inflammatory factors and low levels of homeostatic neuroprotective factors. The genetic signatures of an uncompensated preinflammatory state and ARD progression identified here aid in understanding the susceptible genetic loci that underlie pathogenic mechanisms of age-associated disorders, including several human blinding diseases. IntroductionAge-related disorders arise from failure of tissue maintenance and repair pathways that are accelerated by certain inherited and acquired factors (1). Long-lived nondividing cells, such as neurons, have markedly reduced tolerance to damage (2), and thus exhibit the most pronounced age-related changes. Neuronal cells in the retina are an especially attractive model system to study this phenomenon, owing to their accessibility and wellunderstood physiology. Rod and cone photoreceptors are retinal neuronal cells that initiate visual perception, a function requiring a competent neighboring retinal pigmented epithelium (RPE) for their normal operation (3). In postmitotic cells such as these photoreceptor and RPE cells, cellular senescence can ensue when shed oxidized photoreceptor outer segments (POS) are inadequately phagocytosed and digested by the RPE. This results in accumulation of damaged proteins, formation of toxic metabolic byproducts, inflammatory cell invasion, and cell death. RPE cells are the most affected because, in addition to processing POS, they serve as the conduit between photoreceptors and the choroidal blood supply for metabolite exchange (4). Acquisition of senescence-associated pathology stimulates cells to secrete various factors that contribute to tissue dysfunction. Conversely, adequate clearance of such cells can delay the onset of age-related tissue pathology (5).Aging laboratory experimental animals are important models for studying age-related pathology, especially neurodegenerative disorders, which have been shown to be affected by their genetic backgrounds (6, 7). The A/J inbred mouse ...

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“…Recent studies also support existence of endogenous dsRNA present in the retina as microRNAs (54 -56). In acute light-induced retinal degeneration, nucleic acid-related deposits in the photoreceptor layer were formed that stained with DAPI, Hoechst dyes, and Sytox dye, which together with toluidine blue recognize nucleic acids (57), all suggesting the presence of dsRNA-like endogenous products during this type of tissue degeneration. These data indicate that TLR3 plays a role in both chronic inflammation and ligand-induced RPE/photoreceptor cell death in human retinal diseases.…”

Section: Abca4mentioning

confidence: 99%