Store-operated Orai1 and IP3 receptor-operated TRPC1 channel -: Separation of the Siamese twins

Store-operated channels (SOC) are known to be physiologically activated following agonist-induced IP3 production and depletion of Ca2+ stores. Here we present molecular, biophysical and mechanistic evidence that two ubiquitously expressed plasma membrane channels may be responsible for creating a complex and sometimes controversial SOC image: one being a real SOC encoded by Orai1 and activated exclusively upon depletion of Ca2+ stores ( via iPLA(2)beta-dependent pathway), while the second one is an IP3 receptor-operated channel (IP3ROC) encoded by TRPC1 and activated via its conformational coupling with IP3 receptor. In RBL-2H3 cells endogenously expressing Orai1 and TRPC1, we unmasked and characterized whole-cell current through IP3ROC channels that was hiding behind some familiar fingerprints of I-CRAC, a current through the classical Ca2+-selective SOC (CRAC) channels. We discriminated these currents by their molecular identity, selectivity and different requirements for store depletion, IP3, iPLA(2)beta and conformational coupling to IP3 receptor. New knowledge on the properties and coexistence of Orai1-encoded SOC and TRPC1-encoded IP3ROC, and the use of experimental approaches introduced in this manuscript should help avoid further confusion about these channels, and open new exciting possibilities for their independent studies.