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Paraneurons are endocrine and sensory cells which share structural, functional, and metabolic features with neurons. They produce identical with or related to neurotransmitters or neurohormones, which are synthesized and secreted by regulated secretion. They are receptoconductile-secretory in function, which is shared by specific proteins distributed at proper regions of cell membrane. A substantial advance has been made in the molecular machinery underlying protein sorting and transport within the endoplasmic reticulum and Golgi apparatus, and the mechanism of targeted membrane fusion by constitutive secretion. Various patterns of [Ca2+]c dynamics play cardinal signaling roles in stimulus-secretion coupling in individual secretory cells. Long-lived recurrent Ca2+ spikes or oscillation may maintain prolonged secretory responses, ATP synthesis in mitochondria, cell growth, differentiation, and division. In the neurons and the paraneurons of neuroectodermal origin, action potentials propagate along a conductile region to the secretory region of each cell and hardly be transmitted to the adjacent cells. In the paraneurons of gut endodermal origin, intracellular signalling including Ca2+ spikes can be propagated to the adjacent cells, and in turn may maintain coordination of individual cells forming a cell society.

The effects of lowering extracellular Na+ concentration [Na+]o, on cytosolic Ca2+ concentration, [Ca2+]c were examined by a microfluorimetric method using fura-2 in perifused preparations of isolated rat pancreatic islets. The total replacement of extracellular Na+ (Na+o) by equimolar N-methyl-D-(--)-glucamine caused a rapid rise in [Ca2+]c, and partial replacement of Na+o resulted in correlative rises in [Ca2+]c in accordance with the magnitude of reduced [Na+]o. The rise in [Ca2+]c induced by Na+o removal was strongly inhibited in the Ca2+o-deficient environment or by Ni2+. The [Ca2+]c rise, however, remained almost unchanged in the presence of nifedipine or SK&F 96365, and was enhanced by the addition of ouabain. The electrochemical gradients for Ca2+ (delta mu Ca2+) and Na+ (delta mu Na+) were calculated to be 39.08 and 12.8 kJ/mol, respectively, in this study, indicating a stoichiometry of 3Na+: 1 Ca2+. These results indicate that, in rat pancreatic islets, the rise in [Ca2+]c induced by lowering [Na+]o is mainly due to Ca2+ entry medicated by the Na+/Ca2+ exchanger operating with the stoichiometry of 3Na+:1 Ca2+, and that the Na+/Ca2+ exchanger plays an important role in maintaining stable-state [Ca2+]c.

The mechanism of the potentiating effect of vasoactive intestinal peptide (VIP) on cholecystokinin (CCK-8)-induced amylase release was studied in isolated and perifused pancreatic acini of the guinea pig. VIP (30 pM-10 nM) potentiated CCK-8 (100 pM)-induced amylase release. Unexpectedly, VIP inhibited CCK-8-induced intracellular Ca2+ oscillations. Forskolin (10 microM), an activator of adenylate cyclase, potentiated CCK-8 (100 pM)-induced amylase release with a time course similar to that observed with VIP. Caffeine (20 mM) inhibited both amylase release and Ca2+ oscillations in response to CCK-8, suggesting that inhibition of Ca2+ oscillations does not necessarily lead to a potentiation of amylase release. When intracellular Ca2+ concentration ([Ca2+]c) was raised by thapsigargin (10 microM), a selective inhibitor of Ca(2+)-ATPase in the endoplasmic reticulum (ER), VIP (10 nM) induced significantly greater amylase release than that induced by VIP alone. When [Ca2+]c was lowered by preincubation with BAPTA-AM (25 microM), a cell-permeant Ca2+ chelator, VIP-induced amylase release was completely abolished. These results suggest that VIP, in spite of its inhibitory action on Ca2+ oscillations, facilitates a Ca(2+)-dependent process distal to the increase in [Ca2+]c to potentiate CCK-8-induced amylase release.

Phosphorus nuclear magnetic resonance (31P NMR) spectroscopy was used to study energy supply for protein secretion in the isolated perfused rat pancreas. Stimulation with cholecystokinin (CCK-8) increased fluid secretion and protein output. With 10pM of CCK-8, the tissue contents of ATP, inorganic phosphate (Pi), and creatine phosphate (PCr) remained unchanged. With 100pM of CCK-8, which induced the maximum response in fluid secretion and protein output, Pi increased slightly, ATP and PCr remained almost unchanged. A high dose of CCK-8 (1 nM) suppressed the fluid and protein secretory rates, decreased ATP, and increased Pi significantly, but PCr showed a tendency of increase. Significant changes in ATP and Pi occurred on withdrawal of CCK-8 (1 nM), suggesting activation of ATP hydrolysis for recovery from secretory suppression. During stimulation with 0.1, 0.3, and 3.0 microM of acetylcholine, the similar dose-dependent response was observed in the secretion and the phosphorus metabolism. The present study demonstrated that cytosolic energy metabolism for secretory responses in the pancreas is low and the Lohmann reaction showed less contribution than in the salivary gland. The findings suggest that the energy supply for protein secretion may be cytosolic diffusion of ATP and that the Lohmann reaction system may contribute to synthesis and storing of secretory protein at resting state.

Prolonged perfusion of isolated rat adrenal glands with high K produced a transient increase in adrenaline release that reached a maximum within 1 min and then declined with a half-time of about 5 min. The higher the [K]o used, the larger was the release of adrenaline elicited. There was a linear relation between the mean rate of adrenaline release in the initial 5 min of continuous stimulation with excess K and logarithmic increase in the [K]o. The higher the [Ca]o used, the steeper was relation obtained: the slope determined in the presence of 5 mM-Ca was nearly twice as much as that obtained in the presence of 0.5 mM-Ca. The release of adrenaline in response to excess K was virtually abolished by the omission of [ca]o. The chromaffin cells were depolarized in proportion to logarithmic increase in the [K]o. Linear relations were thus obtained between the mean rates of adrenaline release and the membrane potential of chromaffin cells in the presence of different [Ca]o. Application of high K revived secretory response of a gland after prolonged exposure to acetylcholine in the presence of tetrodotoxin, when adrenaline release had declined below a half of the maximum response. Application of acetylcholine also revived secretory response after prolonged exposure to high K. These results support the view that the mechanism of Ca influx activated by high K may differ from that activated by acetylcholine.

A technique is described for perfusing isolated rat pancreas with a modified Krebs-Henseleit solution. This preparation made feasible the simultaneous measurement of transmembrane potential, effective membrane resistance, rate of flow of pancreatic juice and amylase output. The hyperpolarizing effect of cholecystokinin-pancreozymin (CCK-PZ) was confirmed by perfusion with a solution containing 5 mU CCK-PZ/ml. The hyperpolarizing efffect of CCK-PZ was enhanced when the pancreas was perfused with an oxygenated solution containing dog erythrocytes. This effect was inhibited by ouabain and anaerobic conditions. It is suggested that the oxidative metabolism supplies energy for a mechanism which is responsible for the hyperpolarizing effect of CCK-PZ. The amylase output and the rate of flow of pancreatic juice were enhanced concurrently under conditions that augumented the hyperpolarizing effect, and they were inhibited under conditions that suppressed the effect. Cellular events in stimulus-secretion coupling in the pancreatic acinar cell are discussed by correlating the electrophysiological responses and the secretory responses under various conditions.

By means of an improved type of suction electrode with a fine tip, the characteristic action potential (A-V potential) was recorded from the A-V groove of the heart of toad. The features of A-V potential as distinct from those of the atrium and ventricle were as follows: the rising velocity of upstroke was low, its amplitude was small (5mV on the average as contrasted to 40mV in the atrial or ventricular action potential) and the peak of spike was rounded. The A-V groove was not everywhere conductile, but the conduction was confined in two, well circumscribed areas (about 1mm×1mm in size) at the dorsal and ventral parts of the A-V groove. They were behind the A-V valve and in close proximity to Bidder's ganglia. In the majority of cases, the dorsal pathway played a dominant role in the A-V conduction. When this pathway was artificially suppressed by some procedures, such as a septal nerve stimulation and topical application of acetylcholine, the ventral pathway took over the role of A-V conduction.By stepwise shifting of the exploring suction electrode carefully from the atrium to the ventricle, it was possible to trace the temporal sequence of excitation along the A-V pathway. The propagation of excitation in the pathway was found to be uniform and the conduction velocity was surprisingly low (ca. 2mm/sec at 15°C). The normal A-V delay is thus due to an extremely slow but uniform conduction in the A-V conducting pathway. In antidromic conduction, the V-A conduction was also found to be uniform but its velocity was usually lower than in orthodromic conduction. The uniform conduction through the pathway was well maintained even when the A-V interval was markedly prolonged at low temperature.Increase in driving rate, however, changed the uniform conduction in the pathway into a decremental conduction. This is considered to be due to a slow recovery of excitability (long refractoriness) of fibers in the A-V pathway.