STIM1 activation of adenylyl cyclase 6 connects Ca 2+ and cAMP signaling during melanogenesis

EMBO J. 2018 Mar 1;37(5):e97597. doi: 10.15252/embj.201797597. Epub 2018 Jan 8.


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 STIM1 (stromal interaction molecule 1) interacts with the plasma membrane-localized adenylyl cyclase 6 (ADCY6) to govern melanogenesis. The physiological stimulus α-melanocyte-stimulating hormone (αMSH) depletes ER Ca2+ stores, thus recruiting STIM1 to ER-PM junctions, which in turn activates ADCY6. Using zebrafish as a model system, we further established STIM1's significance in regulating pigmentation in vivo STIM1 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 αMSH-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.

Keywords: cAMP; ADCY6; Orai1; STIM1; pigmentation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism*
  • Animals
  • Calcium / metabolism
  • Calcium Signaling / physiology*
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Proliferation / genetics
  • Cyclic AMP / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation
  • Gene Expression Profiling
  • Melanocytes / cytology
  • Melanocytes / metabolism*
  • Mice
  • ORAI1 Protein / metabolism
  • Skin Pigmentation / genetics*
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism*
  • Zebrafish
  • alpha-MSH / metabolism


  • ORAI1 Protein
  • Stromal Interaction Molecule 1
  • alpha-MSH
  • Cyclic AMP
  • Adenylyl Cyclases
  • adenylyl cyclase 6
  • Calcium