NAADP

NAADP, short for nicotinic acid adenine dinucleotide phosphate, is a potent intracellular calcium-mobilizing second messenger. It functions alongside other messengers such as IP3 and cyclic ADP-ribose to regulate cellular calcium signals. Unlike some messengers that release calcium from the endoplasmic reticulum, NAADP primarily triggers calcium release from acidic intracellular stores, notably lysosome-related organelles, through the endolysosomal network.

Synthesis and metabolism: NAADP is formed from NADP+ by ADP-ribosyl cyclases, with CD38 and related enzymes playing a prominent role. The formation involves a base-exchange reaction that uses nicotinic acid. Once produced, NAADP signaling is tightly controlled by rapid degradation through cellular hydrolases, limiting the duration of the signal.

Mechanism of action: NAADP acts on channels located on the membranes of endolysosomal compartments. The two-pore channels, TPC1 and TPC2, are widely regarded as the primary NAADP receptors in many cell types; their opening causes Ca2+ release from lysosomal stores. The resulting local Ca2+ signal can then trigger wider Ca2+ waves through calcium-induced calcium release mechanisms involving the endoplasmic reticulum, including IP3 receptors and ryanodine receptors, depending on cell type and context.

Physiological and research relevance: NAADP signaling participates in diverse processes such as secretion, muscle contraction, fertilization, and immune cell activity. It is also a focus of pharmacological research, with tools like NAADP analogs and TPC inhibitors (for example, Ned-19) used to study its role. Abnormal NAADP signaling has been implicated in various physiological and pathological states, making it a potential target for therapeutic intervention.