TRPC1 contributes to the Ca²⁺-dependent regulation of adenylate cyclases

SOCE (store-operated Ca²⁺ entry) is mediated via specific plasma membrane channels in response to ER (endoplasmic reticulum) Ca²⁺ store depletion. This route of Ca²⁺ entry is central to the dynamic interplay between Ca²⁺ and cAMP signalling in regulating the activity of Ca²⁺-sensitive adenylate cyclase isoforms (AC1, AC5, AC6 and AC8). Two proteins have been identified as key components of SOCE: STIM1 (stromal interaction molecule 1), which senses ER Ca²⁺ store content and translocates to the plasma membrane upon store depletion, where it then activates Orai1, the pore-forming component of the CRAC (Ca²⁺ release-activated Ca²⁺) channel. Previous studies reported that co-expression of STIM1 and Orai1 in HEK-293 (human embryonic kidney 293) cells enhances Ca²⁺-stimulated AC8 activity and that AC8 and Orai1 directly interact to enhance this regulation. Nonetheless, the additional involvement of TRPC (transient receptor potential canonical) channels in SOCE has also been proposed. In the present study, we evaluate the contribution of TRPC1 to SOCE-mediated regulation of Ca²⁺-sensitive ACs in HEK-293 cells stably expressing AC8 (HEK-AC8) and HSG (human submandibular gland) cells expressing an endogenous Ca²⁺-inhibited AC6. We demonstrate a role for TRPC1 as an integral component of SOCE, alongside STIM1 and Orai1, in regulating Ca²⁺ fluxes within AC microdomains and influencing cAMP production.