A novel Ca²⁺-mediated cross-talk between endoplasmic reticulum and acidic organelles: Implications for NAADP-dependent Ca²⁺ signalling

Nicotinic acid adenine dinucleotide phosphate (NAADP) serves as the ideal trigger of spatio-temporally complex intracellular Ca²⁺ signals. However, the identity of the intracellular Ca²⁺ store(s) recruited by NAADP, which may include either the endolysosomal (EL) or the endoplasmic reticulum (ER) Ca²⁺ pools, is still elusive. Here, we show that the Ca²⁺ response to NAADP was suppressed by interfering with either EL or ER Ca²⁺ sequestration. The measurement of EL and ER Ca²⁺ levels by using selectively targeted aequorin unveiled that the preventing ER Ca²⁺ storage also affected ER Ca²⁺ loading and vice versa. This indicates that a functional Ca²⁺-mediated cross-talk exists at the EL-ER interface and exerts profound implications for the study of NAADP-induced Ca²⁺ signals. Extreme caution is warranted when dissecting NAADP targets by pharmacologically inhibiting EL and/or the ER Ca²⁺ pools. Moreover, Ca²⁺ transfer between these compartments might be essential to regulate vital Ca²⁺-dependent processes in both organelles.