title: 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.
authors.affiliation: Department of Pharmacology, CB2 1QJ, Cambridge, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Bak
authors.forename: R A
authors.initials: RA
authors.lastname: Billington
authors.forename: G
authors.initials: G
authors.lastname: Timar
authors.forename: A C
authors.initials: AC
authors.lastname: Dutton
authors.forename: A A
authors.initials: AA
authors.lastname: Genazzani
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives*; D004110:Diltiazem / Q000494:pharmacology; D007202:Indicators and Reagents / Q000494:pharmacology; D007700:Kinetics; D008861:Microsomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism*; D011485:Protein Binding; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012430:Ruthenium Red / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D007202:Indicators and Reagents; D011956:Receptors, Cell Surface; D012430:Ruthenium Red; D036563:Cyclic ADP-Ribose; C082175:8-aminoadenosine cyclic 3',5'-(hydrogen phosphate) 5'-ribofuranosyl ester; D012433:Ryanodine; D000246:Adenosine Diphosphate Ribose; D009249:NADP; C024376:NAADP; D014700:Verapamil; D004110:Diltiazem; D002118:Calcium