In normal translocation, idle translocons are engaged with ribosome nascent chain complexes, but co-translational translocation has not yet started. There is no evidence that idle translocons are Ca²⁺ permeable. Translocons ‘breathe' along the lateral gate, rapidly transitioning between the idle and intermediate states. We propose that the intermediate state may become transiently Ca²⁺ permeable due to its open structure and the partial displacement of the plug helix. Once the signal peptide of the nascent chain functionally engages with the lateral gate of Sec61α, the protein-conducting channel facilitates the translocation of the nascent protein by complete unfolding of the plug into a disordered state, but the translocating state is not permeable to Ca²⁺ due to the peptide filling the resultant channel. After translocation, Sec61 complexes transiently remain in this fully open post-translocation state, but without a nascent chain, allowing Ca²⁺ ions to permeate through the aqueous channel. The cycle is completed when the ribosomes de-attach and Sec61 complexes return to the ribosome-free or idle state, depending on whether the ribosome is released. Mycolactone traps translocons in an inhibited state, that resembles the intermediate state, but may also be able to bind Sec61α in the idle state. This locks the Sec61 translocon in a Ca²⁺-permeable conformation and an inefficient cycling through the other states, resulting in enhanced Ca²⁺ leak from the ER. Mycolactone causes an increase in membrane-associated 80S ribosomal monosomes. Hence, another contributing factor to the enhanced Ca²⁺ leak could be sustained dwell time in the post-translocation state, due to decreased efficiency of ribosome release.