A Role for ABCC4 in Regulating Pigment Granule Aggregation in Mice

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

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The rosy locus in Drosophila melanogaster: xanthine dehydrogenase and eye pigments.

Genetics ◽

10.1093/genetics/129.4.1099 ◽

1991 ◽

Vol 129 (4) ◽

pp. 1099-1109 ◽

Cited By ~ 4

Author(s):

A G Reaume ◽

D A Knecht ◽

A Chovnick

Keyword(s):

Drosophila Melanogaster ◽

Structural Integrity ◽

Present Report ◽

Specific Interaction ◽

Pigment Granule ◽

Ultrastructural Localization ◽

Xanthine Dehydrogenase ◽

Pigment Formation ◽

Antibody Staining ◽

Pigment Granules

Abstract The rosy gene in Drosophila melanogaster codes for the enzyme xanthine dehydrogenase (XDH). Mutants that have no enzyme activity are characterized by a brownish eye color phenotype reflecting a deficiency in the red eye pigment. Xanthine dehydrogenase is not synthesized in the eye, but rather is transported there. The present report describes the ultrastructural localization of XDH in the Drosophila eye. Three lines of evidence are presented demonstrating that XDH is sequestered within specific vacuoles, the type II pigment granules. Histochemical and antibody staining of frozen sections, as well as thin layer chromatography studies of several adult genotypes serve to examine some of the factors and genic interactions that may be involved in transport of XDH, and in eye pigment formation. While a specific function for XDH in the synthesis of the red, pteridine eye pigments remains unknown, these studies present evidence that: (1) the incorporation of XDH into the pigment granules requires specific interaction between a normal XDH molecule and one or more transport proteins; (2) the structural integrity of the pigment granule itself is dependent upon the presence of a normal balance of eye pigments, a notion advanced earlier.

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Vertebrate melanophores as potential model for drug discovery and development: A review

Cellular & Molecular Biology Letters ◽

10.2478/s11658-010-0044-y ◽

2011 ◽

Vol 16 (1) ◽

Cited By ~ 19

Author(s):

Saima Salim ◽

Sharique Ali

Keyword(s):

Drug Discovery ◽

High Throughput Screening ◽

Skin Pigmentation ◽

Physiological Mechanism ◽

Pigment Granule ◽

Pharmaceutical Products ◽

Surface Receptors ◽

Pigment Granules ◽

Intracellular Signals ◽

Specific Receptors

AbstractDrug discovery in skin pharmacotherapy is an enormous, continually expanding field. Researchers are developing novel and sensitive pharmaceutical products and drugs that target specific receptors to elicit concerted and appropriate responses. The pigment-bearing cells called melanophores have a significant contribution to make in this field. Melanophores, which contain the dark brown or black pigment melanin, constitute an important class of chromatophores. They are highly specialized in the bidirectional and coordinated translocation of pigment granules when given an appropriate stimulus. The pigment granules can be stimulated to undergo rapid dispersion throughout the melanophores, making the cell appear dark, or to aggregate at the center, making the cell appear light. The major signals involved in pigment transport within the melanophores are dependent on a special class of cell surface receptors called G-protein-coupled receptors (GPCRs). Many of these receptors of adrenaline, acetylcholine, histamine, serotonin, endothelin and melatonin have been found on melanophores. They are believed to have clinical relevance to skin-related ailments and therefore have become targets for high throughput screening projects. The selective screening of these receptors requires the recognition of particular ligands, agonists and antagonists and the characterization of their effects on pigment motility within the cells. The mechanism of skin pigmentation is incredibly intricate, but it would be a considerable step forward to unravel its underlying physiological mechanism. This would provide an experimental basis for new pharmacotherapies for dermatological anomalies. The discernible stimuli that can trigger a variety of intracellular signals affecting pigment granule movement primarily include neurotransmitters and hormones. This review focuses on the role of the hormone and neurotransmitter signals involved in pigment movement in terms of the pharmacology of the specific receptors.

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Protein kinase C activation antagonizes melatonin-induced pigment aggregation in Xenopus laevis melanophores.

The Journal of Cell Biology ◽

10.1083/jcb.119.6.1515 ◽

1992 ◽

Vol 119 (6) ◽

pp. 1515-1521 ◽

Cited By ~ 46

Author(s):

D Sugden ◽

S J Rowe

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Xenopus Laevis ◽

Pigment Granule ◽

Melatonin Receptors ◽

Kinase C ◽

Pigment Granules ◽

Slow Aggregation ◽

Pigment Aggregation ◽

Induced Aggregation

The pineal hormone, melatonin (5-methoxy N-acetyltryptamine) induces a rapid aggregation of melanin-containing pigment granules in isolated melanophores of Xenopus laevis. Treatment of melanophores with activators of protein kinase C (PKC), including phorbol esters, mezerein and a synthetic diacylglycerol, did not affect pigment granule distribution but did prevent and reverse melatonin-induced pigment aggregation. This effect was blocked by an inhibitor of PKC, Ro 31-8220. The inhibitory effect was not a direct effect on melatonin receptors, per se, as the slow aggregation induced by a high concentration of an inhibitor of cyclic AMP-dependent protein kinase (PKA), adenosine 3',5'-cyclic monophosphothioate, Rp-diastereomer (Rp-cAMPS), was also reversed by PKC activation. Presumably activation of PKC, like PKA activation, stimulates the intracellular machinery involved in the centrifugal translocation of pigment granules along microtubules. alpha-Melanocyte stimulating hormone (alpha-MSH), like PKC activators, overcame melatonin-induced aggregation but this response was not blocked by the PKC inhibitor, Ro 31-8220. This data indicates that centrifugal translocation (dispersion) of pigment granules in Xenopus melanophores can be triggered by activation of either PKA, as occurs after alpha-MSH treatment, or PKC. The very slow aggregation in response to inhibition of PKA with high concentrations of Rp-cAMPS, suggests that the rapid aggregation in response to melatonin may involve multiple intracellular signals in addition to the documented Gi-mediated inhibition of adenylate cyclase.

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Polarized pigment granule transport occurs in the absence of microtubules in squirrelfish erythrophores: studies of the effects of estramustine

Journal of Cell Science ◽

10.1242/jcs.87.4.565 ◽

1987 ◽

Vol 87 (4) ◽

pp. 565-580

Author(s):

M.E. Stearns ◽

M. Wang

Keyword(s):

Pigment Granule ◽

Electron Microscopic ◽

Microtubule Associated Proteins ◽

Voltage Electron ◽

Associated Proteins ◽

Drug Inhibition ◽

Microscopic Studies ◽

10 Nm Filaments ◽

Inhibition Studies

We have re-examined the involvement of microtubules in the process of pigment granule transport in squirrelfish erythrophores in situ (i.e. on scales). Light-microscopic studies revealed that following exposure to 5 microM-nocodazole for 1 h at 4 degrees C erythrophores retained an ability to aggregate and disperse their pigment uniformly, though at reduced rates. Serial thick-section stereo high-voltage electron-microscopic studies showed that the entire microtubule population was removed by drug treatment and that the microtubules were not reassembled as a result of pigment translocation processes in the presence of reduced levels of nocodazole (0.4 microM). Immunofluorescence microscopic studies confirmed that nocodazole (0.5-1 microM) produced rapid disassembly of the microtubules. Whole-mount electron-microscopic studies showed that the pigment granules were suspended in a cross-linking network of 3–10 nm filaments, which appeared to support ordered pigment transport in situ in the absence of microtubules. Drug inhibition studies showed that micromolar levels of estramustine, a novel anti-MAPs (microtubule-associated proteins) drug, reversibly inhibited pigment transport. The results suggest that an estramustine-sensitive cytomatrix component might produce polarized pigment transport in intact erythrophores.

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CYTOCHALASIN B AND PIGMENT GRANULE TRANSLOCATION

The Journal of Cell Biology ◽

10.1083/jcb.52.3.754 ◽

1972 ◽

Vol 52 (3) ◽

pp. 754-758 ◽

Cited By ~ 27

Author(s):

Joseph McGuire ◽

Gisela Moellmann ◽

Frank McKeon

Keyword(s):

Cytochalasin B ◽

Pigment Granule

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Thioredoxin-family protein EYE2 and Ser/Thr kinase EYE3 play interdependent roles in eyespot assembly

Molecular Biology of the Cell ◽

10.1091/mbc.e10-11-0918 ◽

2011 ◽

Vol 22 (9) ◽

pp. 1421-1429 ◽

Cited By ~ 15

Author(s):

Joseph S. Boyd ◽

Telsa M. Mittelmeier ◽

Mary Rose Lamb ◽

Carol L. Dieckmann

Keyword(s):

De Novo ◽

Pigment Granule ◽

Chloroplast Envelope ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Pigment Granules ◽

Environmental Light ◽

Unicellular Green Alga ◽

Family Protein ◽

Light Stimuli

The eyespot of the biflagellate unicellular green alga Chlamydomonas reinhardtii is a complex organelle that facilitates directional responses of the cell to environmental light stimuli. The eyespot, which assembles de novo after every cell division and is associated with the daughter four-membered (D4) microtubule rootlet, comprises an elliptical patch of rhodopsin photoreceptors on the plasma membrane and stacks of carotenoid-rich pigment granule arrays in the chloroplast. Two loci, EYE2 and EYE3, define factors involved in the formation and organization of the eyespot pigment granule arrays. Whereas EYE3, a serine/threonine kinase of the ABC1 family, localizes to pigment granules, EYE2 localization corresponds to an area of the chloroplast envelope in the eyespot. EYE2 is positioned along, and adjacent to, the D4 rootlet in the absence of pigment granules. The eyespot pigment granule array is required for maintenance of the elliptical shape of both the overlying EYE2 and channelrhodopsin-1 photoreceptor patches. We propose a model of eyespot assembly wherein rootlet and photoreceptor direct EYE2 to an area of the chloroplast envelope, where it acts to facilitate assembly of pigment granule arrays, and EYE3 plays a role in the biogenesis of the pigment granules.

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