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The Many Faces of G Protein-Coupled Receptor 143, an Atypical Intracellular Receptor

Bueschbell, Beatriz; Manga, Prashiela; Schiedel, Anke C
GPCRs transform extracellular stimuli into a physiological response by activating an intracellular signaling cascade initiated via binding to G proteins. Orphan G protein-coupled receptors (GPCRs) hold the potential to pave the way for development of new, innovative therapeutic strategies. In this review we will introduce G protein-coupled receptor 143 (GPR143), an enigmatic receptor in terms of classification within the GPCR superfamily and localization. GPR143 has not been assigned to any of the GPCR families due to the lack of common structural motifs. Hence we will describe the most important motifs of classes A and B and compare them to the protein sequence of GPR143. While a precise function for the receptor has yet to be determined, the protein is expressed abundantly in pigment producing cells. Many GPR143 mutations cause X-linked Ocular Albinism Type 1 (OA1, Nettleship-Falls OA), which results in hypopigmentation of the eyes and loss of visual acuity due to disrupted visual system development and function. In pigment cells of the skin, loss of functional GPR143 results in abnormally large melanosomes (organelles in which pigment is produced). Studies have shown that the receptor is localized internally, including at the melanosomal membrane, where it may function to regulate melanosome size and/or facilitate protein trafficking to the melanosome through the endolysosomal system. Numerous additional roles have been proposed for GPR143 in determining cancer predisposition, regulation of blood pressure, development of macular degeneration and signaling in the brain, which we will briefly describe as well as potential ligands that have been identified. Furthermore, GPR143 is a promiscuous receptor that has been shown to interact with multiple other melanosomal proteins and GPCRs, which strongly suggests that this orphan receptor is likely involved in many different physiological actions.
PMID: 35495622
ISSN: 2296-889x
CID: 5215802

Evidence for Protein-Protein Interaction between Dopamine Receptors and the G Protein-Coupled Receptor 143

Bueschbell, Beatriz; Manga, Prashiela; Penner, Erika; Schiedel, Anke C
Protein-protein interactions between G protein-coupled receptors (GPCRs) can augment their functionality and increase the repertoire of signaling pathways they regulate. New therapeutics designed to modulate such interactions may allow for targeting of a specific GPCR activity, thus reducing potential for side effects. Dopamine receptor (DR) heteromers are promising candidates for targeted therapy of neurological conditions such as Parkinson's disease since current treatments can have severe side effects. To facilitate development of such therapies, it is necessary to identify the various DR binding partners. We report here a new interaction partner for DRD2 and DRD3, the orphan receptor G protein-coupled receptor 143 (GPR143), an atypical GPCR that plays multiple roles in pigment cells and is expressed in several regions of the brain. We previously demonstrated that the DRD2/ DRD3 antagonist pimozide also modulates GPR143 activity. Using confocal microscopy and two FRET methods, we observed that the DRs and GPR143 colocalize and interact at intracellular membranes. Furthermore, co-expression of wildtype GPR143 resulted in a 57% and 67% decrease in DRD2 and DRD3 activity, respectively, as determined by β-Arrestin recruitment assay. GPR143-DR dimerization may negatively modulate DR activity by changing affinity for dopamine or delaying delivery of the DRs to the plasma membrane.
PMID: 34361094
ISSN: 1422-0067
CID: 5004312

The Unfolded Protein and Integrated Stress Response in Melanoma and Vitiligo

Manga, Prashiela; Choudhury, Noshin
Epidermal melanocytes are constantly exposed to environmental stressors such as ultraviolet light (UV) and chemotoxins. Several evolutionarily conversed survival mechanisms are deployed to ensure melanocyte recovery after damage including the unfolded protein response (UPR) and integrated stress response (ISR). The UPR/ISR promote restoration of homeostasis, by modulating transcription and translation as well as activating Nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant activity. If repair fails, the UPR/ISR either stimulate cell death, or adaptation that can lead to survival of damaged cells and promote disease. For example, the UPR/ISR may support melanomagenesis by allowing UV-damaged, mutated cells to survive and adapt to a hostile tumor microenvironment that subjects cells to hypoxia, nutrient deprivation and sub-optimal pH. The UPR and ISR can also promote transcriptional changes that support tumor growth and/or metastasis. Furthermore, these pathways may also underlie acquisition of chemoresistance and modulation of protein expression that alters the efficacy of immunotherapies. UPR activation has also been implicated in the pathogenesis of vitiligo and may promote increased expression of chemokines such as interleukin 6 and interleukin 8 that trigger an autoimmune response against melanocytes. We herein review the potential roles of the UPR/ISR in the etiology of melanoma and vitiligo.
PMID: 33215847
ISSN: 1755-148x
CID: 4673122

IPCC2020-Advancing melanocyte science and friendship in the Land of the Rising Sun [Editorial]

Manga, Prashiela; Suzuki, Tamio; Hayashi, Masahiro
PMID: 33682372
ISSN: 1755-148x
CID: 4809052

Melanocyte stress response pathways in the onset of vitiligo [Meeting Abstract]

Manga, P; Vega, M; Orlow, S J
Vitiligo is an acquired condition that affects about 1% of the world's population and is defined by macular depigmentation of the skin that develops following melanocyte death. Vitiligo has a significant impact on both the physical and mental health of patients. While autoimmune-mediated destruction of melanocytes ultimately leads to depigmentation, the mechanisms that promote vitiligo onset remain poorly defined. We have been investigating the hypothesis that melanocytes from individuals genetically prone to develop vitiligo are less efficient in protecting against cellular traumas such as chemical exposure, which triggers an immune response against them. We delineated the response of melanocytes from normally pigmented individuals (NMs) to challenge with the topical agent monobenzone (monobenzyl ether of hydroquinone or MBEH). Three key stress response pathways were activated by MBEH exposure: the unfolded protein stress response (UPR), the NRF2-regulated antioxidant response and the nuclear factor-kappa B (NFkappaB) pathway. We established a key role for the UPR and NRF2 pathways in determining melanocyte viability and demonstrated disruption of their activity in melanocytes from individuals who developed vitiligo (VMs). We further showed that the NFkappaB pathway contributes to an increase in expression of IL6 and IL8 following NM exposure to MBEH and that expression of these chemokines is higher in VMs compared to NMs. These chemokines can promote an autoimmune response. We have now used transcriptome analysis to identify additional stress response pathways that are dysfunctional in vitiligo. Our data suggest that multiple signaling pathways that protect cells against trauma and facilitate a return to homeostasis are disrupted in VMs and may cause these cells to be targeted by the immune system
ISSN: 1755-148x
CID: 4828112

Biophysical Compatibility of a Heterotrimeric Tyrosinase-TYRP1-TYRP2 Metalloenzyme Complex

Lavinda, Olga; Manga, Prashiela; Orlow, Seth J; Cardozo, Timothy
Tyrosinase (TYR) is a copper-containing monooxygenase central to the function of melanocytes. Alterations in its expression or activity contribute to variations in skin, hair and eye color, and underlie a variety of pathogenic pigmentary phenotypes, including several forms of oculocutaneous albinism (OCA). Many of these phenotypes are linked to individual missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. We previously showed that two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Accordingly, to investigate whether TYR, TYRP1, and TYRP2 are biophysically compatible with various heterocomplexes, we computationally docked a high-quality 3D model of TYR to the crystal structure of TYRP1 and to a high-quality 3D model of TYRP2. Remarkably, the resulting TYR-TYRP1 heterodimer was complementary in structure and energy with the TYR-TYRP2 heterodimer, with TYRP1 and TYRP2 docking to different adjacent surfaces on TYR that apposed a third realistic protein interface between TYRP1-TYRP2. Hence, the 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex. In addition, this heterotrimeric TYR-TYRP1-TYRP2 positioned the C-terminus of each folded enzymatic domain in an ideal position to allow their C-terminal transmembrane helices to form a putative membrane embedded three-helix bundle. Finally, pathogenic TYR mutations causing OCA1A, which also destabilize TYR biochemically, cluster on an unoccupied protein interface at the periphery of the heterotrimeric complex, suggesting that this may be a docking site for OCA2, an anion channel. Pathogenic OCA2 mutations result in similar phenotypes to those produced by OCA1A TYR mutations. While this complex may be difficult to detect in vitro, due to the complex environment of the vertebrate cellular membranous system, our results support the existence of a heterotrimeric complex in melanogenesis.
PMID: 33995009
ISSN: 1663-9812
CID: 4876532

Vitiligo and Melanoma-Associated Vitiligo: Understanding Their Similarities and Differences

Cohen, Brandon E; Manga, Prashiela; Lin, Krysta; Elbuluk, Nada
BACKGROUND:There has been a significant increase in the number and efficacy of therapies for advanced melanoma. Immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 inhibitors, have improved the prognosis for patients with advanced melanoma. While spontaneous melanoma-associated vitiligo is a known phenomenon, the occurrence of melanoma-associated vitiligo following melanoma therapy is now recognized to associate with favorable outcomes. OBJECTIVE:The objective of this article is to provide a comprehensive literature review of melanoma-associated vitiligo and explore the insights these findings provide about the pathobiology of vitiligo and mechanisms underlying melanoma therapies. METHODS:PubMed and Science Direct databases were searched for studies pertaining to melanoma-associated vitiligo. The 36 studies reviewed included meta-analyses (n = 2), prospective cohort studies (n = 4), prospective observational studies (n = 3), retrospective studies (n = 12), case series (n = 2), and case reports (n = 13). RESULTS:The basic mechanisms underlying melanoma-associated vitiligo and vitiligo may be shared. Characterization of these mechanisms will identify new biomarkers and therapeutic targets for both melanoma and vitiligo. CONCLUSIONS:Co-opting the immune system to target tumor antigens highlights the potential overlap between anti-tumor immunity and autoimmunity. The development of vitiligo-like depigmentation in association with immunotherapy for melanoma may provide insights into both the immune response against melanoma as well as the pathogenesis of vitiligo.
PMID: 32468356
ISSN: 1179-1888
CID: 4451972

Proceeding Report of the Second Vitiligo International Symposium (VIS)- November 9-10, 2018, Detroit, Michigan, USA

Lyons, Alexis B; Ghia, Deepti; Abdallah, Marwa; Abdel-Malek, Zalfa; Esmat, Samia; Ezzedine, Khaled; Grimes, Pearl; Harris, John E; Lui, Harvey; Manga, Prashiela; Mi, Qing-Sheng; Pandya, Amit; Parsad, Davinder; Passeron, Thiery; Picardo, Mauro; Seneschal, Julien; Silpa-Archa, Narumol; Taieb, Alain; Xiang, Flora; Lim, Henry W; Hamzavi, Iltefat H
The Global Vitiligo Foundation (GVF) hosted the 2nd Biennial Vitiligo International Symposium (VIS), which was held at the Detroit Marriott at Renaissance Center in Detroit, Michigan, USA from November 9-10, 2018. The conference was opened by Iltefat H. Hamzavi (Detroit, Michigan, USA), President of the GVF and Co-Chair of the VIS and David M. Ozog (Detroit, Michigan, USA), C.S. Livingood Chair and Chairman of the Department of Dermatology of Henry Ford Hospital, Detroit, Michigan, USA. Henry W. Lim (Detroit, Michigan, USA), former President of the American Academy of Dermatology, Chair Emeritus of the Department of Dermatology of Henry Ford Hospital, and Co-Chair of the VIS, then presented highlights of the meeting. The meeting was organized around four plenary lectures, several diverse panel discussions, and workshops emphasizing vitiligo surgery and imaging.
PMID: 31984599
ISSN: 1755-148x
CID: 4293842

Melanoma to Vitiligo: The Melanocyte in Biology & Medicine-Joint Montagna Symposium on the Biology of Skin/PanAmerican Society for Pigment Cell Research Annual Meeting

Leachman, Sancy A; Hornyak, Thomas J; Barsh, Greg; Bastian, Boris C; Brash, Douglas E; Cleaver, James E; Cooper, Cynthia D; D'Orazio, John A; Fujita, Mayumi; Holmen, Sheri L; Indra, Arup K; Kramer, Kenneth H; Le Poole, I Caroline; Lo, Roger S; Lund, Amanda W; Manga, Prashiela; Pavan, William J; Setaluri, Vijayasaradhi; Stemwedel, Clara E; Kulesz-Martin, Molly F
PMID: 31348921
ISSN: 1523-1747
CID: 3988362

Children with oculocutaneous albinism in Africa: Characteristics, challenges and medical care

Kromberg, J. G.R.; Manga, P.; Kerr, R.
Oculocutaneous albinism (OCA) is an inherited condition characterised by significantly reduced pigment in skin, hair and eyes, visual defects and an increased risk of skin cancer. In the South African black population, 1 in 4 000 people is affected. Quality of life in children with albinism is influenced not only by health problems, but also by stigmatisation, rejection and cultural issues. This review aims to explore the latest literature available on the epidemiology, genetics, clinical characteristics, psychosocial issues and possible management strategies, focusing on affected children. The knowledge provided here is required of health professionals if a more fully informed service is to be offered to these children and their families.
ISSN: 1994-3032
CID: 4462482