NAADP receptors are present and functional in the heart

Abstract

Alongside the well-studied inositol 1,4,5 trisphosphate and ryanodine receptors, evidence is gathering that a new intracellular release mechanism, gated by the pyridine nucleotide nicotinic acid adenine dinucleotide phosphate (NAADP), is present in numerous organisms, ranging from plant to mammalian cells (reviewed in [1]). Most cells have been shown to express at least two Ca(2+)-release mechanisms controlled by different messengers, and this can lead to redundancy, convergence, or divergence of responses. One exception appears to be muscle and heart contractile tissues. Here, it is thought that the dominant intracellular channel is the ryanodine receptor, while IP(3) receptors are poorly expressed and their role appears to be negligible. We now report that NAADP receptors are functional and abundant in cardiac microsomes. NAADP binds specifically and with high affinity (130 pM and 4 nM) to two sites on cardiac microsomes and releases Ca(2+) with an apparent EC(50) of 323 +/- 14 nM. Furthermore, binding experiments show that this receptor displays both positive and negative cooperativity, a peculiarity unique among intracellular Ca(2+) channels. Therefore, we show that the heart possesses multiple mechanisms to increase the complexity of Ca(2+) signaling and that NAADP may be integral in the functioning of this organ.

NAADP Controls Cross-talk between Distinct Ca2+ Stores in the Heart

“…The NAADP concentration achieved following photorelease is expected to be in this approximate range, probably closer to the lower level, making NAADP remarkably potent with respect to its effects on whole cell Ca 2ϩ transients. This would be consistent with the observed potency of NAADP in other mammalian cells (9,16,18).…”

“…Cardiac tissue expresses high affinity binding sites for NAADP, and NAADP stimulates Ca 2ϩ efflux from microsomal fractions derived from rat heart (9). NAADP is an endogenous molecule, with levels in mouse heart reported to be 0.4 nmol/mg protein (10).…”

Regulation of Intracellular Ca2+ Stores by Multiple Ca2+-Releasing Messengers

“…NAADP is involved in fertilization in ascidian eggs (78), starfish oocytes (79), and sea urchin eggs (30). NAADP is also involved in Ca 2ϩ release in the brain (80) and cardiac microsomes (81), as well as in the control of activation and proliferation of human T-cells (82). It has been shown recently that NAADP enhances quantal neurosecretion at the frog neuromuscular junction (83).…”

Calcium Signaling in Airway Smooth Muscle

“…These enzymes also possess a transglycosidation (base-exchange) activity capable of exchanging the nicotinamide moiety of NAD(P) with nicotinic acid or other nucleophiles. In the presence of nicotinic acid and NADP, the base-exhange reaction of the ADP-ribosyl cyclase family is responsible for generating nicotinic acid adenine dinucleotide phosphate (NAADP), another compound capable of regulating calcium release from intracellular stores in a variety of cell types, including those of some smooth muscles (57)(58)(59)(60)(61)(62).…”