title: NAADP-mediated channel 'chatter' in neurons of the rat medulla oblongata.
abstract: NAADP (nicotinic acid-adenine dinucleotide phosphate) is a potent Ca(2+)-mobilizing messenger that stimulates Ca(2+) release in a variety of cells. NAADP-sensitive Ca(2+) channels are thought to reside on acidic Ca(2+) stores and to be functionally coupled to IP(3) (inositol 1,4,5-trisphosphate) and/or ryanodine receptors located on the endoplasmic reticulum. Whether NAADP-sensitive Ca(2+) channels 'chatter' to other channels, however, is not clear. In the present study, we have used a cell-permeant NAADP analogue to probe NAADP-mediated responses in rat medulla oblongata neurons. NAADP-AM (NAADP-acetoxymethyl ester) evoked global cytosolic Ca(2+) signals in isolated neurons that were reduced in amplitude by removal of external Ca(2+), abolished by disruption of acidic compartments and substantially inhibited by blockade of ryanodine receptors. In rat medullary slices, NAADP-AM depolarized neurons from the nucleus ambiguus in the presence of intracellular EGTA, but not of the faster Ca(2+) chelator BAPTA [1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid]. Depolarization was also dependent upon extracellular Ca(2+), acidic stores and ryanodine receptors. In voltage-clamp mode, NAADP-AM induced an inward current with a reversal potential of approx. 0 mV. The results of the present study reveal the presence of acidic NAADP-sensitive Ca(2+) stores in medulla neurons, the mobilization of which results not only in global Ca(2+) signals but also in local signals that activate non-selective cation channels on the cell surface resulting in depolarization. Thus NAADP is capable of co-ordinating channels both within the cell interior and at the cell membrane representing a novel mechanism for excitation of central neurons.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad St, Philadelphia, PA 19140, USA.
authors.forename: G Cristina
authors.initials: GC
authors.lastname: Brailoiu
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
authors.forename: Raman
authors.initials: R
authors.lastname: Parkesh
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
authors.forename: Grant C
authors.initials: GC
authors.lastname: Churchill
authors.forename: Sandip
authors.initials: S
authors.lastname: Patel
authors.forename: Nae J
authors.initials: NJ
authors.lastname: Dun
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004594:Electrophysiology; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism*; D008526:Medulla Oblongata; D009249:NADP / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007473:Ion Channels; C531084:nicotinic acid adenine dinucleotide phosphate acetoxymethyl ester; D009249:NADP; C024376:NAADP; D002118:Calcium