Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation

Maftuna Yusupova; Dalee Zhou; Jaewon You; Jeydi Gonzalez-Guzman; Megha B. Ghanta; Hong Pu; Zalfa Abdel-Malek; Qiuying Chen; Steven S. Gross; John D'Orazio; Shosuke Ito; Kazumasa Wakamatsu; Melissa L. Harris; Jonathan H. Zippin

doi:10.1016/j.jid.2023.04.011

Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation

Maftuna Yusupova
, Dalee Zhou
, Jaewon You
, Jeydi Gonzalez-Guzman
, Megha B. Ghanta
, Hong Pu
, Zalfa Abdel-Malek
, Qiuying Chen
, Steven S. Gross
, John D'Orazio
, Shosuke Ito
, Kazumasa Wakamatsu
, Melissa L. Harris
, Jonathan H. Zippin

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways—the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway—affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications. However, whether MC1R genotype affects melanosomal pH is poorly understood. We now report that loss of function MC1R does not affect melanosomal pH. Thus, sAC signaling appears to be the only cAMP signaling pathway that regulates melanosomal pH. We also addressed whether MC1R genotype affects sAC-dependent regulation of melanin synthesis. Although sAC loss of function in wild-type human melanocytes stimulates melanin synthesis, sAC loss of function has no effect on melanin synthesis in MC1R nonfunctional human and mouse melanocytes or skin and hair melanin in e/e mice. Interestingly, activation of transmembrane adenylyl cyclases, which increases epidermal eumelanin synthesis in e/e mice, leads to enhanced production of eumelanin in sAC-knockout mice relative to that in sAC wild-type mice. Thus, MC1R- and sAC-dependent cAMP signaling pathways define distinct mechanisms that regulate melanosomal pH and pigmentation.

Original language	English
Pages (from-to)	2019-2029.e3
Journal	Journal of Investigative Dermatology
Volume	143
Issue number	10
DOIs	https://doi.org/10.1016/j.jid.2023.04.011
State	Published - Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Funding

The authors thank members of the Zippin laboratory for critical reading of the manuscript. The melan-e cell lines were obtained from the Functional Genomics Cell Bank at St. George's, University of London. JHZ was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (1 R01 AR077664-01A1). DZ was funded by the Weill Cornell/Rockefeller/Memorial Sloan-Kettering Tri-Institutional MD-PhD Program. The research performed by the Harris Laboratory was funded by the University of Alabama at Birmingham Biology Departmental Start-up funds (to MLH). ZA laboratory was funded by VA Merit Award (l0BX003668). QC was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR076029) and the National Institute of Environmental Health Sciences (R21 ES032347). Conceptualization: MY, DZ, MLH, JZ; Data Curation: MY, DZ, JY, JGG, MBG, QC, SI, KW; Formal Analysis: MY, DZ, JY, QC, SI, KW, MLH, JHZ; Funding Acquisition: JHZ; Investigation: MY, DZ, JY, JGG, MBG, QC, SI, KW; Methodology: QC, SSG, JD, MLH, JHZ; Project Administration: SSG, KW, MLH, JHZ; Resources: ZAM, QC, SSG, HP, JD; Supervision: SSG, MLH, JHZ; Validation: QC, SI, KW, MLH, JHZ; Visualization: MY, DZ, JY, JGG, MBG, ZAM, QC, KW, MLH, JHZ; Writing – Original Draft Preparation: MY, DZ, MLH, JHZ; Writing - Review and Editing: MY, DZ, JD, SI, KW, MLH, JHZ The authors thank members of the Zippin laboratory for critical reading of the manuscript. The melan-e cell lines were obtained from the Functional Genomics Cell Bank at St. George's, University of London. JHZ was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases ( 1 R01 AR077664-01A1 ). DZ was funded by the Weill Cornell/Rockefeller/Memorial Sloan-Kettering Tri-Institutional MD-PhD Program. The research performed by the Harris Laboratory was funded by the University of Alabama at Birmingham Biology Departmental Start-up funds (to MLH). ZA laboratory was funded by VA Merit Award (l0BX003668). QC was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases ( R01AR076029 ) and the National Institute of Environmental Health Sciences ( R21 ES032347 ).

Funders	Funder number
National Institutes of Health/National Institute of Environmental Health Sciences	R21 ES032347
National Institutes of Health/National Institute of Environmental Health Sciences
National Institute of Arthritis and Musculoskeletal and Skin Diseases	1 R01 AR077664-01A1
National Institute of Arthritis and Musculoskeletal and Skin Diseases
U.S. Department of Veterans Affairs	R01AR076029, l0BX003668
U.S. Department of Veterans Affairs
University of Alabama
St George's University of London

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Dermatology
Cell Biology

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10.1016/j.jid.2023.04.011

Cite this

Yusupova, M., Zhou, D., You, J., Gonzalez-Guzman, J., Ghanta, M. B., Pu, H., Abdel-Malek, Z., Chen, Q., Gross, S. S., D'Orazio, J., Ito, S., Wakamatsu, K., Harris, M. L., & Zippin, J. H. (2023). Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation. Journal of Investigative Dermatology, 143(10), 2019-2029.e3. https://doi.org/10.1016/j.jid.2023.04.011

@article{c9a41f9708474ea7bd96367356ef9e8a,

title = "Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation",

abstract = "cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways—the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway—affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications. However, whether MC1R genotype affects melanosomal pH is poorly understood. We now report that loss of function MC1R does not affect melanosomal pH. Thus, sAC signaling appears to be the only cAMP signaling pathway that regulates melanosomal pH. We also addressed whether MC1R genotype affects sAC-dependent regulation of melanin synthesis. Although sAC loss of function in wild-type human melanocytes stimulates melanin synthesis, sAC loss of function has no effect on melanin synthesis in MC1R nonfunctional human and mouse melanocytes or skin and hair melanin in e/e mice. Interestingly, activation of transmembrane adenylyl cyclases, which increases epidermal eumelanin synthesis in e/e mice, leads to enhanced production of eumelanin in sAC-knockout mice relative to that in sAC wild-type mice. Thus, MC1R- and sAC-dependent cAMP signaling pathways define distinct mechanisms that regulate melanosomal pH and pigmentation.",

author = "Maftuna Yusupova and Dalee Zhou and Jaewon You and Jeydi Gonzalez-Guzman and Ghanta, \{Megha B.\} and Hong Pu and Zalfa Abdel-Malek and Qiuying Chen and Gross, \{Steven S.\} and John D'Orazio and Shosuke Ito and Kazumasa Wakamatsu and Harris, \{Melissa L.\} and Zippin, \{Jonathan H.\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = oct,

doi = "10.1016/j.jid.2023.04.011",

language = "English",

volume = "143",

pages = "2019--2029.e3",

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Yusupova, M, Zhou, D, You, J, Gonzalez-Guzman, J, Ghanta, MB, Pu, H, Abdel-Malek, Z, Chen, Q, Gross, SS, D'Orazio, J, Ito, S, Wakamatsu, K, Harris, ML & Zippin, JH 2023, 'Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation', Journal of Investigative Dermatology, vol. 143, no. 10, pp. 2019-2029.e3. https://doi.org/10.1016/j.jid.2023.04.011

TY - JOUR

T1 - Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation

AU - Yusupova, Maftuna

AU - Zhou, Dalee

AU - You, Jaewon

AU - Gonzalez-Guzman, Jeydi

AU - Ghanta, Megha B.

AU - Pu, Hong

AU - Abdel-Malek, Zalfa

AU - Chen, Qiuying

AU - Gross, Steven S.

AU - D'Orazio, John

AU - Ito, Shosuke

AU - Wakamatsu, Kazumasa

AU - Harris, Melissa L.

AU - Zippin, Jonathan H.

PY - 2023/10

Y1 - 2023/10

N2 - cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways—the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway—affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications. However, whether MC1R genotype affects melanosomal pH is poorly understood. We now report that loss of function MC1R does not affect melanosomal pH. Thus, sAC signaling appears to be the only cAMP signaling pathway that regulates melanosomal pH. We also addressed whether MC1R genotype affects sAC-dependent regulation of melanin synthesis. Although sAC loss of function in wild-type human melanocytes stimulates melanin synthesis, sAC loss of function has no effect on melanin synthesis in MC1R nonfunctional human and mouse melanocytes or skin and hair melanin in e/e mice. Interestingly, activation of transmembrane adenylyl cyclases, which increases epidermal eumelanin synthesis in e/e mice, leads to enhanced production of eumelanin in sAC-knockout mice relative to that in sAC wild-type mice. Thus, MC1R- and sAC-dependent cAMP signaling pathways define distinct mechanisms that regulate melanosomal pH and pigmentation.

AB - cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways—the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway—affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications. However, whether MC1R genotype affects melanosomal pH is poorly understood. We now report that loss of function MC1R does not affect melanosomal pH. Thus, sAC signaling appears to be the only cAMP signaling pathway that regulates melanosomal pH. We also addressed whether MC1R genotype affects sAC-dependent regulation of melanin synthesis. Although sAC loss of function in wild-type human melanocytes stimulates melanin synthesis, sAC loss of function has no effect on melanin synthesis in MC1R nonfunctional human and mouse melanocytes or skin and hair melanin in e/e mice. Interestingly, activation of transmembrane adenylyl cyclases, which increases epidermal eumelanin synthesis in e/e mice, leads to enhanced production of eumelanin in sAC-knockout mice relative to that in sAC wild-type mice. Thus, MC1R- and sAC-dependent cAMP signaling pathways define distinct mechanisms that regulate melanosomal pH and pigmentation.

UR - https://www.scopus.com/pages/publications/85165010965

UR - https://www.scopus.com/pages/publications/85165010965#tab=citedBy

U2 - 10.1016/j.jid.2023.04.011

DO - 10.1016/j.jid.2023.04.011

M3 - Article

C2 - 37142186

AN - SCOPUS:85165010965

SN - 0022-202X

VL - 143

SP - 2019-2029.e3

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 10

ER -

Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

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Cite this