title: Catecholamine exocytosis during low frequency stimulation in mouse adrenal chromaffin cells is primarily asynchronous and controlled by the novel mechanism of Ca2+ syntilla suppression.
abstract: Adrenal chromaffin cells (ACCs), stimulated by the splanchnic nerve, generate action potentials (APs) at a frequency near 0.5 Hz in the resting physiological state, at times described as 'rest and digest'. How such low frequency stimulation in turn elicits sufficient catecholamine exocytosis to set basal sympathetic tone is not readily explained by the classical mechanism of stimulus-secretion coupling, where exocytosis is synchronized to AP-induced Ca(2+) influx. By using simulated action potentials (sAPs) at 0.5 Hz in isolated patch-clamped mouse ACCs, we show here that less than 10% of all catecholaminergic exocytosis, measured by carbon fibre amperometry, is synchronized to an AP. The asynchronous phase, the dominant phase, of exocytosis does not require Ca(2+) influx. Furthermore, increased asynchronous exocytosis is accompanied by an AP-dependent decrease in frequency of Ca(2+) syntillas (i.e. transient, focal Ca(2+) release from internal stores) and is ryanodine sensitive. We propose a mechanism of disinhibition, wherein APs suppress Ca(2+) syntillas, which themselves inhibit exocytosis as they do in the case of spontaneous catecholaminergic exocytosis.
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Lefkowitz
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: DeCrescenzo
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
authors.forename: Kailai
authors.initials: K
authors.lastname: Duan
authors.affiliation: Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA, 01655, USA Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
authors.forename: Karl D
authors.initials: KD
authors.lastname: Bellve
authors.affiliation: Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA, 01655, USA Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Fogarty
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01655, USA Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA, 01655, USA John.Walsh@umassmed.edu.
authors.forename: John V
authors.initials: JV
authors.lastname: Walsh
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01655, USA Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
authors.forename: Ronghua
authors.initials: R
authors.lastname: ZhuGe
mesh_terms: D000200:Action Potentials; D000311:Adrenal Glands / Q000166:cytology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002395:Catecholamines / Q000378:metabolism*; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D018408:Patch-Clamp Techniques; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism
chemical_list: D002395:Catecholamines; D019837:Ryanodine Receptor Calcium Release Channel; C000592748:ryanodine receptor 2. mouse; D002118:Calcium