Two-pore calcium channel protein (TPC) (TPC)

The NAADP-sensitive receptor, primarily identified as the Two-pore calcium channel protein (TPC) family (specifically TPCN1 and TPCN2), is a class of intracellular ion channels located on acidic organelles such as endosomes and lysosomes (UniProt Q8NHX9, Q9ULQ1). These channels are activated by nicotinic acid adenine dinucleotide phosphate (NAADP), the most potent known calcium-mobilizing second messenger (Galione, 2015). Recent evidence suggests that NAADP does not bind directly to TPCs but acts through accessory proteins like JPT2 and LSM12 to trigger channel opening (Gunaratne et al., 2021). This signaling pathway is essential for endolysosomal trafficking, autophagy, and nutrient sensing, and its disruption is linked to metabolic diseases like diabetes and fatty liver disease. In infectious disease, TPCs are required for the endosomal escape and entry of viruses such as Ebola and SARS-CoV-2 (Sakurai et al., 2015). Pharmacological inhibitors like tetrandrine and Ned-19 have been shown to block these processes, making the NAADP-sensitive receptor a significant target for antiviral and metabolic therapies (Naylor et al., 2009).

Other names

Nicotinic acid adenine dinucleotide phosphate receptorTPCN1TPCN2Two-pore channelNAADP receptor

Antagonism of NAADP-mediated calcium release from acidic organelles by either blocking the NAADP binding site on accessory proteins (like JPT2) or inhibiting the TPC channel pore directly.