STIM1 activation of adenylyl cyclase 6 connects Ca2+ and cAMP signaling during melanogenesis

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 Ca 2+ 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 Ca 2+ 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. Synopsis Interaction of the endoplasmic reticulum (ER) calcium sensor STIM1 with Orai channels at the plasma membrane mediates cellular calcium influx after its depletion from ER stores. New data show that adenylyl cyclase 6 (ADCY6) is an Orai‐independent STIM1 interactor at ER–plasma membrane junctions with a critical role in melanogenesis. STIM1 regulates pigmentation independently of Orai channels. α‐MSH induces ER Ca 2+ release and STIM1 activation that in turn regulates pigmentation. STIM1 interacts with ADCY6 and stimulates its activity to increase cAMP generation and melanogenesis. STIM1 Ser/Pro‐rich domain mediates the interaction with ADCY6. Graphical Abstract α‐Melanocyte‐stimulating hormone induces interaction of calcium sensor STIM1 with ADCY6 at endoplasmic reticulum–plasma membrane junctions to increase cAMP synthesis and promote pigmentation.