Progesterone receptor membrane component 1 facilitates Ca²⁺ signal amplification between endosomes and the...

Membrane contact sites (MCSs) between endosomes and the endoplasmic reticulum (ER) are thought to act as specialized trigger zones for Ca²⁺ signaling, where local Ca²⁺ released via endolysosomal ion channels is amplified by ER Ca²⁺-sensitive Ca²⁺ channels into global Ca²⁺ signals. Such amplification is integral to the action of the second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). However, functional regulators of inter-organellar Ca²⁺ crosstalk between endosomes and the ER remain poorly defined. Here, we identify progesterone receptor membrane component 1 (PGRMC1), an ER transmembrane protein that undergoes a unique heme-dependent dimerization, as an interactor of the endosomal two pore channel, TPC1. NAADP-dependent Ca²⁺ signals were potentiated by PGRMC1 overexpression through enhanced functional coupling between endosomal and ER Ca²⁺ stores and inhibited upon PGRMC1 knockdown. Point mutants in PGMRC1 or pharmacological manipulations that reduced its interaction with TPC1 were without effect. PGRMC1 therefore serves as a TPC1 interactor that regulates ER-endosomal coupling with functional implications for cellular Ca²⁺ dynamics and potentially the distribution of heme.