NAADP Receptors

Abstract

Of the established Ca2+-mobilizing messengers, NAADP is arguably the most tantalizing. It is the most potent, often efficacious at low nanomolar concentrations, and its receptors undergo dramatic desensitization. Recent studies have identified a new class of calcium-release channel, the two-pore channels (TPCs), as the likely targets for NAADP regulation, even though the effect may be indirect. These channels localized at endolysosomes, where they mediate local Ca2+ release, and have highlighted a new role of acidic organelles as targets for messenger-evoked Ca2+ mobilization. Three distinct roles of TPCs have been identified. The first is to effect local Ca2+ release that may play a role in endolysosomal function including vesicular fusion and trafficking. The second is to trigger global calcium release by recruiting Ca2+-induced Ca2+-release (CICR) channels at lysosomal–endoplasmic reticulum (ER) junctions. The third is to regulate plasma membrane excitability by the targeting of Ca2+ release from appropriately positioned subplasma membrane stores to regulate plasma membrane Ca2+-activated channels. In this review, I discuss the role of nicotinic acid adenine nucleotide diphosphate (NAADP)-mediated Ca2+ release from endolysosomal stores as a widespread trigger for intracellular calcium signaling mechanisms, and how studies of TPCs are beginning to enhance our understanding of the central role of lysosomes in Ca2+ signaling.

COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches

“…TPCs are gated by multiple agonists, including nicotinic acid adenine dinucleotide phosphate (NAADP), sphingosine, and the EL phospholipid, phosphatidylinositol 3,5-bisphosphate (Galione 2019). TPCs-mediated Ca 2+ release recruits EL-located Ca 2+sensitive decoders, including calmodulin, synaptotagmin VII, and Arf6 (Faris et al 2018), to regulate vesicular fusion and trafficking (Galione 2019). A screening campaign aiming at repurposing FDA-approved drugs as novel antiviral compounds recently revealed that classical Ca 2+ antagonists blocked Ebola virus and MERS-CoV infections in vitro (Sakurai et al 2015;Gunaratne et al 2018a, b).…”

Lysosomal Fusion: An Efficient Mechanism Increasing Their Sequestration Capacity for Weak Base Drugs without Apparent Lysosomal Biogenesis

“…This issue must be studied further. Similarly, it is unclear which ion channel was responsible for Ca 2+ release, as inside the lysosomal membrane, there are several calcium channels that serve as NAADP receptors, including the two pore channels 1 and 2 (TPC1, 2) with high affinity for NAADP, and transient receptor potential melastatin 2 (TRPM2) with low affinity for NAADP [43]. Which of these channels are involved in NAADP-induced Ca 2+ release has yet to be elucidated.…”

Role of Protons in Calcium Signaling

“…For some time, studies on the role of protons in cellular processes have taken into consideration the relationship between pH and calcium and its effects, in particular in relation to cellular channels and organelles. Protons modulate the action of various types of channel, including voltage-gated proton channels [DeCoursey 2018] which extrude protons, the Orai/STIM, transient receptor potential (TRP) channels [Yu 2018, Vangeel 2019, and two pore channels (TPC) [Kintzer 2018, Galione 2019] which foster Ca 2+ influx via store-operated calcium entry (SOCE). Sarco-endoplasmic reticulum Ca 2+ -ATPase pump (SERCA) and the plasma membrane Ca 2+ -ATPase pump (PMCA) remove excess Ca 2+ from the cytosol.…”

“…To our knowledge, no study attributes a triggering role to protons or makes an in-depth biochemical investigation of the interdependence mechanism between the H + and Ca 2+ ions. Nonetheless, significant progress has been made over the past 40 years or so: several fundamental second messengers and pathways for calcium signaling have been identified [Pozzan 1994, Clapham 2007, Berridge 2012, Balla 2013, Carafoli 2016, Galione 2019, and the understanding of specific receptors [Rossi 2018 and channels [Kozak andPutney 2017, Galione 2019] has improved. Experimental methods, particularly calcium imaging techniques, have been developed [Depaoli 2019, Siciliano 2019.…”