Different binding property of STIM1 and its novel splice variant STIM1L to Orai1, TRPC3, and TRPC6 channels

Stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum (ER) Ca2+ sensor to control ER Ca2+ levels. A recent study has shown that STIM1L, a new splice variant of STIM1, is expressed in various tissues of rodent and in human skeletal muscle, and that the interaction of STIM1L with actin filament allows rapid activation of store-operated Ca2+ entry (SOCE) mediated through Orai1 channels. Here, we characterize mRNA expression and function of human STIM1 and STIM1L, and compare their binding property to Orai1 functioning as store-operated Ca2+ channels (SOCCs), and TRPC3 (transient receptor potential canonical 3) and TRPC6 channels functioning as endothelin type A receptor (ETAR)-operated Ca2+ channels (ROCCs). Although mRNA for STIM1 was ubiquitously expressed in human tissues, STIM1L was detected only in skeletal muscle. STIM1L augmented thapsigargin- and endothelin-1-induced SOCE more strongly than STIM1 in human embryonic kidney 293 cells stably expressing ETAR, whereas, it tends to suppress ETAR-operated Ca2+ entry (ROCE) via TRPC3 and TRPC6 more strongly than STIM1. Coimmunoprecipitation experiments have revealed that when compared with STIM1, STIM1L binds more abundantly to Orai1 and also to TRPC3 and TRPC6. These results suggest that the higher binding capacity of STIM1L to SOCCs and ROCCs plays an important role in the regulation of Ca2+ signaling such as the augmentation of SOCE via Orai1 and the inhibition of ROCE via TRPC3 and TRPC6.

► STIM1L, a new splice variant of STIM1, is detected only in skeletal muscle in human.
► STIM1 and STIM1L bind to Orai1, TRPC3, and TRPC6.
► Binding capacity of STIM1L to Orai1, TRPC3, and TRPC6 is higher than that of STIM1.
► Augmentation of store-operated Ca2+ entry by STIM1L is greater than that by STIM1.
► STIM1L tends to suppress receptor-operated Ca2+ entry more strongly than STIM1.