STIM-TRP Pathways and Microdomain Organization: Ca²⁺ Influx Channels: The Orai-STIM1-TRPC Complexes

Ca²⁺ influx by plasma membrane Ca²⁺ channels is the crucial component of the receptor-evoked Ca²⁺ signal. The two main Ca²⁺ influx channels of non-excitable cells are the Orai and TRPC families of Ca²⁺ channels. These channels are activated in response to cell stimulation and Ca²⁺ release from the endoplasmic reticulum (ER). The protein that conveys the Ca²⁺ content of the ER to the plasma membrane is the ER Ca²⁺ sensor STIM1. STIM1 activates the Orai channels and is obligatory for channel opening. TRPC channels can function in two modes, as STIM1-dependent and STIM1-independent. When activated by STIM1, both channel types function at the ER/PM (plasma membrane) junctions. This chapter describes the properties and regulation of the channels by STIM1, with emphasis how and when TRPC channels function as STIM1-dependent and STIM1-independent modes and their unique Ca²⁺-dependent physiological functions that are not shared with the Orai channels.