A central concept in the physiology of neurosecretion is that a rise in cytosolic [Ca2+] in the vicinity of plasmalemmal Ca2+ channels due to Ca2+ influx elicits exocytosis. Here, we examine the effect on spontaneous exocytosis of a rise in focal cytosolic [Ca2+] in the vicinity of ryanodine receptors (RYRs) due to release from internal stores in the form of Ca2+ syntillas. Ca2+ syntillas are focal cytosolic transients mediated by RYRs, which we first found in hypothalamic magnocellular neuronal terminals. (scintilla, Latin for spark; found in nerve terminals, normally synaptic structures.) We have also observed Ca2+ syntillas in mouse adrenal chromaffin cells. Here, we examine the effect of Ca2+ syntillas on exocytosis in chromaffin cells. In such a study on elicited exocytosis, there are two sources of Ca2+: one due to influx from the cell exterior through voltage-gated Ca2+ channels, and that due to release from intracellular stores. To eliminate complications arising from Ca2+ influx, we have examined spontaneous exocytosis where influx is not activated. We report here that decreasing syntillas leads to an increase in spontaneous exocytosis measured amperometrically. Two independent lines of experimentation each lead to this conclusion. In one case, release from stores was blocked by ryanodine; in another, stores were partially emptied using thapsigargin plus caffeine, after which syntillas were decreased. We conclude that Ca2+ syntillas act to inhibit spontaneous exocytosis, and we propose a simple model to account quantitatively for this action of syntillas.

The type 1 ryanodine receptor (RyR1) is expressed widely in the brain, with high levels in the cerebellum, hippocampus, and hypothalamus.

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Key pointsr Although the importance of asynchronous exocytosis is becoming clearer, not enough is known about its roles and mechanisms.r Here we describe the nature of exocytosis in mouse adrenal chromaffin cells during low frequency physiological stimulation, i.e. 0.5 Hz, providing new views.r We report that less than 10% of all catecholaminergic exocytosis during low frequency stimulation is synchronized to a simulated action potential (sAP), i.e. the dominant phase is asynchronous.r This asynchronous phase of exocytosis does not require Ca 2+ influx, requires the ryanodine receptor, RyR2, and comprises exocytic events with characteristics similar to those of spontaneous events.r We propose a novel mechanism of disinhibition wherein APs inhibit Ca 2+ syntillas, relieving their inhibition of spontaneous exocytosis, which leads to an increase in the asynchronous phase of elicited exocytosis.r The work has the specific physiological implication that basal sympathetic tone associated with the 'rest and digest' state is set in part by Ca 2+ syntillas. Furthermore, there is evidence that this regulation of exocytosis by Ca 2+ syntillas may be a general mechanism that extends to neurons.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.

Here we describe an atypical presentation of progressive dysphagia in a 72-year-old man leading to frequent regurgitations over the course of 30 years. Investigations revealed a foreign body ring surrounding the proximal stomach and dilation of the oesophagus proximal to the gastro-oesophageal junction. An Angelchik device was extracted; however, the patient’s rapid deterioration prior to surgery, in addition to his severely dysfunctional oesophagus, required placement of a jejunostomy feeding tube. Device removal was complicated by prior abdominal surgery, necessitating a thoracic approach. This case offers guidance on the management of patients with Angelchik prostheses who develop similar complications, while drawing attention to the importance and difficulties of early, definitive diagnosis in oesophageal pathology such as achalasia and gastro-oesophageal reflux disease.

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