Endothelin-B receptor-mediated Ca

Kang, Hyun-Woo; Kang, Won-Hyoung; Lee, C.-O.

doi:10.1007/s004240050522

Cited by 5 publications

(5 citation statements)

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“…Thus, our data suggests that these two pathways do not act in concert all the time. This is supported by the finding of a constitutively active GNAQ mutation in an NF1 +/− uveal melanoma, which otherwise might be redundant, if EDNRB/GNAQ signaling completely overlapped with NF1 [8], [9].…”

Section: Discussionmentioning

confidence: 74%

“…Ednrb is activated by the Endothelin 3 ( Edn3 ) ligand [7]. Endothelin signaling transmits survival/proliferation signals into melanocytes by way of heterotrimeric G proteins, including the alpha subunits, Gnaq and Gna11 [8], [9]. Mice lacking either Edn3 or Ednrb have a very similar phenotype and are hypo-pigmented due to a lack of melanocytes during development [10], [11], [12].…”

Section: Introductionmentioning

confidence: 99%

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Genetic Interactions between Neurofibromin and Endothelin Receptor B in Mice

2013

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When mutations in two different genes produce the same mutant phenotype, it suggests that the encoded proteins either interact with each other, or act in parallel to fulfill a similar purpose. Haploinsufficiency of Neurofibromin and over-expression of Endothelin 3 both cause increased numbers of melanocytes to populate the dermis during mouse development, and thus we are interested in how these two signaling pathways might intersect. Neurofibromin is mutated in the human genetic disease, neurofibromatosis type 1, which is characterized by the development of Schwann cell based tumors and skin hyper-pigmentation. Neurofibromin is a GTPase activating protein, while the Endothelin 3 ligand activates Endothelin receptor B, a G protein coupled receptor. In order to study the genetic interactions between endothelin and neurofibromin, we defined the deletion breakpoints of the classical Ednrb piebald lethal allele (Ednrbs-l) and crossed these mice to mice with a loss-of-function mutation in neurofibromin, Dark skin 9 (Dsk9). We found that Neurofibromin haploinsufficiency requires Endothelin receptor B to darken the tail dermis. In contrast, Neurofibromin haploinsufficiency increases the area of the coat that is pigmented in Endothelin receptor B null mice. We also found an oncogenic mutation in the G protein alpha subunit, GNAQ, which couples to Endothelin receptor B, in a uveal melanoma from a patient with neurofibromatosis type 1. Thus, this data suggests that there is a complex relationship between Neurofibromin and Endothelin receptor B.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Genetic Interactions between Neurofibromin and Endothelin Receptor B in Mice

2013

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“…In addition, the accompanying changes to calcium gradients in the Golgi lumen could impactanumberofprocesses,includingtheactivationofcalciumdependent furin-like protease activity in a manner analogous to the melanosomal model proposed by Lamason et al (7). The Golgi Ca 2ϩ may also act as a store for Ca 2ϩ -mediated signaling such as the proposed melanogenic response to agouti signaling protein (43) or the UV-induced response to endothelin-1 (44). Ca 2ϩ is also a co-factor for phenylalanine hydroxylase (45); the latter has been suggested to protect the redox balance and prevent DNA damage (46).…”

Section: Discussionmentioning

confidence: 99%

SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis

Ginger

Askew

Ogborne

et al. 2008

Journal of Biological Chemistry

145

126

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A non-synonymous single nucleotide polymorphism in the human SLC24A5 gene is associated with natural human skin color variation. Multiple sequence alignments predict that this gene encodes a member of the potassium-dependent sodium-calcium exchanger family denoted NCKX5. In cultured human epidermal melanocytes we show using affinity-purified antisera that native human NCKX5 runs as a triplet of approximately 43 kDa on SDS-PAGE and is partially localized to the trans-Golgi network. Removal of the NCKX5 protein through small interfering RNA-mediated knockdown disrupts melanogenesis in human and murine melanocytes, causing a significant reduction in melanin pigment production. Using a heterologous expression system, we confirm for the first time that NCKX5 possesses the predicted exchanger activity. Site-directed mutagenesis of NCKX5 and NCKX2 in this system reveals that the non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue that is important for NCKX5 and NCKX2 activity. We suggest that NCKX5 directly regulates human epidermal melanogenesis and natural skin color through its intracellular potassium-dependent exchanger activity.

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“…In human kidney 293 cells, EDN3 increased GTP binding of Gα 13 ( Kitamura et al, 1999 ). In the cellular context of melanocytes, the treatment of a cell line expressing EDNRB with EDN3 increased inositol 1,4,5-triphosphate and intra-cytoplasmic calcium concentrations, which supports a role for Gα q ( Kang et al, 1998 ). These data high-light the promiscuity of Ednrb.…”

Section: The Relationship Between Ednrb and Gα Q/11 mentioning

confidence: 74%

Gnaq and Gna11 in the Endothelin Signaling Pathway and Melanoma

Urtatiz

Raamsdonk

2016

Front. Genet.

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In this article, we first briefly outline the function of G protein coupled receptors in cancer, and then specifically examine the roles of the seven transmembrane G protein coupled Endothelin B receptor (Ednrb) and the G proteins, GNAQ and GNA11, in both melanocyte development and melanoma. Ednrb plays an essential role in melanocyte development. GNAQ and GNA11 are oncogenes when mutated in certain types of melanocytic lesions, being extremely frequent in uveal melanoma, which forms from melanocytes located in the eye. Previously, we reported that in mice, Schwann cell precursor derived melanocytes colonize the dermis and hair follicles, while the inter-follicular epidermis is populated by other melanocytes. A pattern has emerged whereby melanocytes whose activities are affected by gain-of-function mutations of the Endothelin 3 ligand and Gαq/11 are the same subset that arise from Schwann cell precursors. Furthermore, the forced expression of the constitutively active human GNAQQ209L oncogene in mouse melanocytes only causes hyper-proliferation in the subset that arise from Schwann cell precursors. This has led us to hypothesize that in Schwann cell precursor derived melanocytes, Ednrb signals through Gαq/11. Ednrb is promiscuous and may signal through other G protein alpha subunits in melanomas located in the inter-follicular epidermis.

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Endothelin-B receptor-mediated Ca

Cited by 5 publications

References 0 publications

Genetic Interactions between Neurofibromin and Endothelin Receptor B in Mice

Genetic Interactions between Neurofibromin and Endothelin Receptor B in Mice

SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis

Gnaq and Gna11 in the Endothelin Signaling Pathway and Melanoma

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