STIM1 gates TRPC channels, but not Orai1, by electrostatic interaction

Area of Science:

• Cellular biology
• Molecular mechanisms of ion channel gating

Background:

• Receptor-evoked calcium signals involve store-operated channels (SOCs) like TRPC and Orai channels.
• STIM1 is known to gate both TRPC and Orai channels, but the precise gating mechanisms remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanism by which STIM1 gates the TRPC1 channel.
• To determine if STIM1 employs the same gating mechanism for TRPC and Orai channels.

Main Methods:

• Investigated the interaction between STIM1 and TRPC1 using charge-swapping mutations.
• Performed functional analysis of mutated STIM1 and TRPC1 proteins.
• Compared STIM1 gating mechanisms for TRPC1 and Orai1.

Main Results:

• STIM1 gates TRPC1 through intermolecular electrostatic interactions between conserved charged residues (STIM1 KK684-685 and TRPC1 DD639-640).
• Specific charge orientation is crucial, but reciprocal charge combinations enable functional gating.
• STIM1 also gates TRPC3 via a similar electrostatic mechanism.
• STIM1 gates Orai1 through a distinct mechanism not requiring STIM1's polybasic and S/P domains.

Conclusions:

• STIM1 utilizes an electrostatic interaction mechanism to gate TRPC1 and TRPC3 channels.
• The gating mechanism for Orai1 by STIM1 is different from that of TRPC channels.
• This study reveals distinct molecular strategies employed by STIM1 for gating different SOC families.