page_title: Nicotinic acid adenine dinucleotide phosphate
section_title: Ca2+ uptake
hierarchical_section_title: Nicotinic acid adenine dinucleotide phosphate / Target organelle / Ca2+ uptake
caption_attribution_description: English: Speculative Ca2+ uptake mechanisms into acidic vesicles.
context_page_description: Nicotinic acid adenine dinucleotide phosphate, is a Ca²⁺-mobilizing second messenger synthesised in response to extracellular stimuli. Like its mechanistic cousins, IP₃ and cyclic adenosine diphosphoribose, NAADP binds to and opens Ca²⁺ channels on intracellular organelles, thereby increasing the intracellular Ca²⁺ concentration which, in turn, modulates sundry cellular processes. Structurally, it is a dinucleotide that only differs from the house-keeping enzyme cofactor, NADP by a hydroxyl group and yet this minor modification converts it into the most potent Ca²⁺-mobilizing second messenger yet described. NAADP acts across phyla from plants to man.
context_section_description: In other Ca²⁺-storing organelles such as the endoplasmic reticulum or Golgi, stores are filled by calcium ATPase pumps, typified by the ubiquitous members of the SERCA or the SPCA (secretory pathway Ca²⁺-ATPase) families respectively. Ca²⁺ uptake by acidic stores occurs via other proteins: in yeast and plants (the best understood systems) the acidic vacuoles host two uptake pathways: a high affinity Ca²⁺-ATPase and a low affinity Ca²⁺/H⁺ antiporter (or exchanger, generically denoted as CHX). The pumps are different from the SERCA family (and, importantly, are insensitive to their inhibitor, thapsigargin) whereas the exchanger exploit the H⁺ gradient to drive Ca²⁺ uptake against its concentration gradient. The genes encoding these proteins are well-defined.
  In higher organisms, the situation is less clear. Ca²⁺ uptake usually occurs via a thapsigargin-insensitive pathway (therefore precluding SERCA involvement) and appears to be dependent upon the H⁺ gradient; whether this occurs via a single (unknown) CHX or via exchangers in series (e.g. Na⁺/H⁺ exchanger coupled to a Na⁺/Ca²⁺ exchanger) is unproven. Acidic vesicles in some cell types may well take a leaf out of the yeasts'/plants' book and host two uptake pathways, but whether this is a widespread template is unclear.
  In the absence of selective Ca²⁺ uptake inhibitors (often because we do not even know the protein/route), it is common to indirectly inhibit Ca²⁺ uptake by collapsing the thermodynamic drive (the H⁺ gradient). The H⁺ gradient can be eliminated either with H⁺ ionophores (protonophores) such as nigericin or monensin or by inhibiting the V-ATPase that generates the H⁺ gradient with compounds such as bafilomycin A1 or concanamycin.
caption: Simplified pathways regulating luminal Ca2+ (left) and pH (right) in acidic organelles. Ca2+ uptake can be mediated either by a Ca2+/H+ exchanger (CHX, that exploits the pH gradient) or a Ca2+ pump (powered by ATP hydrolysis). The low luminal pH is driven by the H+ pump, the V-ATPase, and aided by essential counterion movements, e.g. chloride uptake, that acts as a charge shunt essential for optimal proton uptake.[citation needed]
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