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STIM 1 activation of adenylyl cyclase 6 connects Ca 2+ and cAMP signaling during melanogenesis

Authors
  • Motiani, Rajender K1
  • Tanwar, Jyoti1
  • Raja, Desingu Ayyappa1, 2
  • Vashisht, Ayushi1
  • Khanna, Shivangi1, 2
  • Sharma, Sachin1, 2
  • Srivastava, Sonali1
  • Sivasubbu, Sridhar1, 2
  • Natarajan, Vivek T1, 2
  • Gokhale, Rajesh S1, 3
  • 1 CSIR‐Institute of Genomics and Integrative Biology, India , (India)
  • 2 Academy of Scientific and Innovative Research, India , (India)
  • 3 National Institute of Immunology, India , (India)
Type
Published Article
Journal
The EMBO Journal
Publisher
EMBO
Publication Date
Jan 08, 2018
Volume
37
Issue
5
Identifiers
DOI: 10.15252/embj.201797597
PMID: 29311116
PMCID: PMC5830913
Source
PubMed Central
Keywords
License
Unknown
External links

Abstract

Endoplasmic reticulum ( ER )–plasma membrane ( PM ) junctions form functionally active microdomains that connect intracellular and extracellular environments. While the key role of these interfaces in maintenance of intracellular Ca2+ levels has been uncovered in recent years, the functional significance of ER ‐ PM junctions in non‐excitable cells has remained unclear. Here, we show that the ER calcium sensor protein STIM 1 (stromal interaction molecule 1) interacts with the plasma membrane‐localized adenylyl cyclase 6 ( ADCY 6) to govern melanogenesis. The physiological stimulus α‐melanocyte‐stimulating hormone (α MSH ) depletes ER Ca2+ stores, thus recruiting STIM 1 to ER ‐ PM junctions, which in turn activates ADCY 6. Using zebrafish as a model system, we further established STIM 1's significance in regulating pigmentation in vivo . STIM 1 domain deletion studies reveal the importance of Ser/Pro‐rich C‐terminal region in this interaction. This mechanism of cAMP generation creates a positive feedback loop, controlling the output of the classical α MSH ‐ cAMP ‐ MITF axis in melanocytes. Our study thus delineates a signaling module that couples two fundamental secondary messengers to drive pigmentation. Given the central role of calcium and cAMP signaling pathways, this module may be operative during various other physiological processes and pathological conditions.

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