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PubMed1985

Co-existence of cholecystokinin- or gastrin-like peptides with other peptides in the hypophysis and the hypothalamus.

The presence of cholecystokinin and gastrin has been reported in the hypothalamohypophyseal system. These peptides present a peculiar distribution in the hypothalamic nuclei, the median eminence, and the neurohypophysis. CCK and gastrin have close relationships with other peptides like oxytocin, CRF, vasopressin, and the enkephalins; these relationships vary in different projecting areas and in different types of hypothalamic neurons. The functional role of G-CCK in neurosecretion seems to be linked to the role of these closely associated peptides and certainly deserves further investigation.

Animals↗
PubMed1993

Osmotic inhibition of neurohypophysial secretion.

Regulation of pituitary AVP and OT secretion is a complex process governed by both osmotic and nonosmotic afferent inputs to the neurohypophysis. Multiple lines of evidence indicate that nonosmotic afferent inputs consist of both excitatory and inhibitory units. Although excitatory osmotic afferent inputs have also been well described, this review summarizes data supporting the existence of sensitive and powerful inhibitory osmotic units as well. The simplistic view that volume regulatory influences on AVP secretion will always take precedence over osmoregulatory influences is clearly not in agreement with the accumulated data regarding osmotic inhibition of neurohypophysial secretion. A more appropriate model is one in which the net effect of these various excitatory and inhibitory influences on magnocellular secretory activity is determined by an integration of the activities of the various afferents, in concert with primary osmoreceptive properties of the magnocellular neurons themselves and other factors that act directly on magnocellular neurons (Fig. 1). The site(s) of action and the chemical nature of pathways subserving osmotic inhibition of neurohypophysial secretion remain to be ascertained. The most likely candidates at this time appear to be GABA projections from the ventral nucleus medianus to the SON and PVN, and endogenous opioid peptides acting either in the hypothalamus or directly at the neural lobe. This conceptual framework is consistent with the results of multiple studies of the interactive effects of osmotic and nonosmotic stimuli on neurohypophysial secretion that have demonstrated mutually interactive effects of these stimuli: volume status affects the threshold and gain of osmoregulated neurohypophysial secretion, and conversely osmotic status affects the magnitude of baroreceptor-mediated neurohypophysial secretion. When excitatory and inhibitory inputs are in conflict, the net effect on neurosecretion appears to be influenced not only by the respective magnitudes of the opposing stimuli, but also by the time course over which the stimuli develop. Consequently, although chronic hypoosmolality causes a potent inhibition of neurohypophysial secretion, acute nonosmotic stimuli of sufficient magnitude are still able to break through this inhibition. These results allow the possibility that clinical states of hypoosmolality due to inappropriate AVP secretion may be due either to the presence of excitatory nonosmotic stimuli that override osmotic inhibition, or alternatively to defects in the pathways or mechanisms underlying the osmotic inhibition itself.

Animals↗
PubMed2002

Computing the chromaffin cell: a research-community curator/user approach to biocomputation for chromaffin cell biology.

Exocytosis, stimulus-secretion coupling, real-time measurements of neurosecretion, and stimulus-secretion-synthesis coupling (stimulus-transcription coupling) were all initially proposed and verified in the chromaffin cell. Detailed analysis of the molecules and pathways responsible for secretion and transsynaptic regulation of gene expression patterns in neuroendoccrine cells have been very fruitfully explored in chromaffin cells and the related PC12 pheochromocytoma cell line, using modern molecular biologcal, cellular imaging, and expression profiling techniques. The time is clearly at hand for a concerted bioinformatics approach to acquiring and synthesizing electrophysiological, biochemical, and proteomic/genomic data on the chromaffin cell. Accelerating this process will fully realize the unique attributes of the chromaffin cell as a homogeneous, accessible, fully functional model of the posttmitotic neuroendocrine cell.

Animals↗
PubMed1975

Catecholamine release from bovine adrenal medulla in response to maintained depolarization.

Prolonged exposure of venous-perfused bovine adrenal glands to high K in the presence of external Ca produces a transient increase in catecholamine output that reaches a maximum after about 1 min and then declines with a half-time of about 1-2 min. 2. The time course of the transient secretory response to high K does not depend appreciably on the total catecholamine output which indicates that depletion of releasable catecholamine is unlikely to be responsible for the transient nature of the response. 3. Application of 3-6 mM-Ba stimulates secretion from a gland after many minutes exposure to high K, when catecholamine output has declined close to resting levels. This provides further evidence that depletion does not play a major role in the transient response and shows that maintained depolarization does not inhibit the secretory mechanism. 4. Exposure to high K solutions in which Ca has been replaced isomotically by Mg does not evoke any catecholamine output. Subsequent application of Ca always elicits some secretion although the size of this response to added Ca declines rapidly during exposure to Ca-free, high K solutions. The failure of the secretory response in these experiments is more rapid, and earlier in onset than the declining phase of the normal secretory response evoked in the presence of calcium. 5. Pre-treatment with Ca-free solutions of intermediate K content reduces the response to subsequent simultaneous application of high K and Ca. There is a roughly sigmoidal relation between the reduction in response and the logarithm of the K concentration used for pre-treatment. 6. Thin slices of bovine adrenal medulla show qualitatively similar responses on exposure to high K. Examination of the flourescent signal from slices dyed with the potential-sensitive dye DiS-C(3)-(5) suggests that maintained exposure to high K produces a stable depolarization. 7. The most likely explanation for these results is that K-depolarization first activates and subsequently inactivates a potential-sensitive Ca permeability channel. This inactivation is time and possibly potential dependent. 8. The effect of high K on calcium movements in medullary slices was examined. Exposure to 72 mM-K increases (45)Ca uptake, the increase being greatest during the first 10 min. The efflux of Ca is also increased on exposure to high K in the presence of Ca. The net Ca uptake in 72 mM-K is smaller than the tracer uptake of Ca. These findings indicate that K depolarization stimulates a Ca-Ca exchange process. They are also consistent with, but do not offer strong positive support for, the idea that K-depolarization first activates and subsequently inactivates Ca entry. 9. It is suggested that Ca inactivation might play a role in the modulation of neurosecretion and neurotransmitter release by changes in membrane potential.

Adrenal Medulla↗
PubMed1985

Dopaminergic modulation of neuromuscular transmission in the prawn.

The action of the putative crustacean neurohormone dopamine was examined in the fast extensor musculature of the prawn with intracellular and extracellular recording techniques. Dopamine produced a concentration-dependent (10(-7)-10(-5) M) decrease in the size of the excitatory junctional potential (e.j.p.). It had no effect on the muscle fibre resting membrane potential or input resistance. High concentrations (10(-5)M) of dopamine had no effect on the amplitude distribution or decay time of quantal unit currents, indicating that the agent does not act by blocking post-synaptic receptors or channels. Bath application of dopamine reduced the quantal content at single release sites with a similar time course and concentration dependence as that observed for the e.j.p. Dopamine had no effect on histograms of synaptic delays determined over a 10 degree C range, indicating that it does not modify the time course of phasic neurosecretion. Twin-impulse facilitation experiments showed a marked decrease in the duration of facilitation in the presence of dopamine. These results are interpreted according to recent theoretical and experimental findings as indicating that the dopamine-induced reduction in transmitter release is produced by a decrease in the entry of Ca during the nerve terminal action potential.

Action Potentials↗
PubMed1987

Requirements for hormone release from permeabilized nerve endings isolated from the rat neurohypophysis.

1. Isolated nerve endings from rat neurohypophyses were permeabilized with digitonin in order to gain access to the cytoplasm. Release of vasopressin (AVP), oxytocin and the neurophysins was studied under different experimental conditions. 2. Hormone release, which occurred by exocytosis, was Ca2+ dependent. Half-maximal release was observed at ca. 1.7 microM-Ca2+ in contrast to ca. 300 microM for K+-induced hormone secretion from non-permeabilized neurosecretosomes. 3. Release also occurred when the neurosecretosomes were challenged with Ca2+ 20 min after digitonin treatment. This suggests that the isolated nerve endings remain permeable after treatment with digitonin. 4. Although hormone release was potentiated in the presence of ATP, and to a lesser extent with guanosine triphosphate (GTP), secretion occurred in the absence of nucleotides. 5. Replacement of K+ as the major cation by Na+ did not modify the secretory response to a Ca2+ challenge. Release, although reduced, still occurred when KCl was replaced by sucrose. 6. Compared to glutamate, Cl-, Br- and I- did not modify the Ca2+-independent release. This release was increased in the presence of SCN-. The order of effectiveness of the anions studied in inhibiting the Ca2+-dependent release was glutamate less than Br- = Cl- = I- less than SCN-. 7. Increasing the osmolarity of the perfusate inhibited the Ca2+-dependent release of AVP and oxytocin. 8. Vincristine, which binds to microtubules, had no effect on the secretory process. 9. Ca2+ dependent AVP release was partially inhibited by the calmodulin antagonist trifluoroperazine. 10. Hormone release was potentiated by the protein kinase C activator, 4-beta-phorbol 12-myristate acetate (TPA). 11. Whereas 0.2 microM-Ca2+ induced a barely significant increase in AVP release, inositol 1,4,5-triphosphate, in the continued presence of 0.2 microM-Ca2+, produced a large secretory response. 12. 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonic acid (SITS), an inhibitor of Cl- permeability, reduced the Ca2+-dependent AVP release. 13. Carbonyl cyanide m-chlorophenylhydrazone (CCCP), which reduces the transmembrane potential of isolated neurohypophysial granules, inhibited the Ca2+-dependent hormone secretion. 14. Maximal hormone release occurred at pH 6.6. 15. It is concluded that the permeabilized neurosecretosomes represent an excellent model for studying the minimal requirements for neurosecretion.

Animals↗
PubMed1995

GABAA receptor activation and the excitability of nerve terminals in the rat posterior pituitary.

1. The activation of GABAA receptors in nerve terminal membranes gates a Cl- channel. Experiments were conducted to determine how the activation of this receptor influences membrane potentials, action potentials and voltage-activated Na+ and K+ channels. 2. When activation of the GABAA receptor produced only conductance changes and no voltage changes, action potentials changed only slightly. The threshold for action potential generation increased by 15%. GABA reduced the broadening of action potentials caused by high frequency stimulation by only 7%. These results indicate that membrane shunting by GABA-gated Cl- channels plays a relatively minor role. 3. By recording changes in the current through K+ channels in cell-attached patches, the activation of GABAA receptors was shown to depolarize the nerve terminal membrane from rest by 14 mV. The GABAB receptor agonist baclofen produced no change in resting membrane potential as measured by this same technique. 4. In whole-terminal recordings under current clamp, with pipettes containing various Cl- concentrations, the GABA-induced depolarization increased with Ecl. The variation with Ecl provided a basis for evaluating the contributions of leak and K+ current in the balance of currents that determines the magnitude of the GABA-induced depolarization. 5. Based on the GABA-induced voltage change and an evaluation of the other currents of significance in the relevant voltage range, an estimate was obtained for ECl of -48 mV to give an estimate for the intracellular Cl- ion concentration of 20 mM. 6. Under conditions allowing both conductance and voltage to change during Cl- channel gating, GABA prevented action potential responses to current injection. Comparable depolarizations produced by adjusting a steady holding current also blocked action potential responses. 7. A depolarization from -60 to -45 mV under voltage clamp inactivated approximately 90% of the Na+ channels and activated a small amount of K+ current. This suggests that inactivation of Na+ channels makes a major contribution to the inhibition of action potentials by GABA. 8. These results are consistent with the hypothesis that GABA inhibits neurosecretion by retarding impulse propagation into the terminal arborization. These results support a depolarization block mechanism for the inhibition of secretion, in which depolarization inactivates Na+ channels sufficiently to block action potentials.

Action Potentials↗
PubMed2002

Physical mobilization of secretory vesicles facilitates neuropeptide release by nerve growth factor-differentiated PC12 cells.

It has been speculated that neurosecretion can be enhanced by increasing the motion, and hence, the availability of cytoplasmic secretory vesicles. However, facilitator-induced physical mobilization of secretory vesicles has not been observed directly in living cells, and recent experimental results call this hypothesis into question. Here, high resolution green fluorescent protein (GFP)-based measurements in nerve growth factor-differentiated PC12 cells are used to test whether altering dense core vesicle (DCV) motion affects neuropeptide release. Experiments with mycalolide B and jasplakinolide demonstrate that neuropeptidergic DCV motion at the ends of processes is proportional to F-actin. Furthermore, Ba2+ increases DCV mobility without detectably modifying F-actin. Finally, we show that altering DCV motion by changing F-actin or stimulating with Ba2+ proportionally changes sustained neuropeptide release. Therefore, increasing DCV mobility facilitates prolonged neuropeptide release.

Actins↗
PubMed2002

Regulation by Rab3A of an endogenous modulator of neurotransmitter release at mouse motor nerve endings.

Rab3A, a small GTP-binding protein attached to synaptic vesicles, has been implicated in several stages in the process of neurosecretion, including a late stage occurring just prior to the actual release of neurotransmitter. The inhibitory neuromodulator adenosine also targets a late step in the neurosecretory pathway. We thus compared neuromuscular junctions from adult Rab3A(-/-) mutant mice with those from wild-type mice with respect to: (a) the basic electrophysiological correlates of neurotransmitter release at different stimulation frequencies, and (b) the actions of exogenous and endogenous adenosine on neurotransmitter release in normal calcium solutions. Neither the spontaneous quantal release of acetylcholine (ACh) nor basal evoked ACh release (0.05 Hz) differed between the mutant and wild-type mice. At 50-100 Hz stimulation (10-19 stimuli), facilitation of release was observed in the mutant mice but not in wild-type, followed by a depression of ACh release in both strains. ACh release at the end of the stimulus train in the mutant mouse was approximately double that of the wild-type mouse. The threshold concentration for inhibition of ACh release by exogenous adenosine was over 20-fold lower in the mutant mouse than in the wild-type mouse. The adenosine A(1) receptor antagonist 8-cyclopentyltheophylline (CPT) increased ACh release (0.05-1 Hz stimulation) in the mutant mouse under conditions in which it had no effect in the wild-type mouse. CPT had no effect on the pattern of responses recorded during repetitive stimulation in either strain. The results suggest that Rab3A reduces the potency of adenosine as an endogenous mediator of neuromuscular depression.

Acetylcholine↗
PubMed2004

Neuroepithelial oxygen chemoreceptors of the zebrafish gill.

In aquatic vertebrates, hypoxia induces physiological changes that arise principally from O(2) chemoreceptors of the gill. Neuroepithelial cells (NECs) of the zebrafish gill are morphologically similar to mammalian O(2) chemoreceptors (e.g. carotid body), suggesting that they may play a role in initiating the hypoxia response in fish. We describe morphological changes of zebrafish gill NECs following in vivo exposure to chronic hypoxia, and characterize the cellular mechanisms of O(2) sensing in isolated NECs using patch-clamp electrophysiology. Confocal immunofluorescence studies indicated that chronic hypoxia (P(O(2)) = 35 mmHg, 60 days) induced hypertrophy, proliferation and process extension in NECs immunoreactive for serotonin or synaptic vesicle protein (SV2). Under voltage clamp, NECs responded to hypoxia (P(O(2)) = 25-140 mmHg) with a dose-dependent decrease in K(+) current. The current-voltage relationship of the O(2)-sensitive current (I(KO(2))) reversed near E(K) and displayed open rectification. Pharmacological characterization indicated that I(KO(2)) was resistant to 20 mM tetraethylammonium (TEA) and 5 mM 4-aminopyridine (4-AP), but was sensitive to 1 mm quinidine. In current-clamp recordings, hypoxia produced membrane depolarization associated with a conductance decrease; this depolarization was blocked by quinidine, but was insensitive to TEA and 4-AP. These biophysical and pharmacological characteristics suggest that hypoxia sensing in zebrafish gill NECs is mediated by inhibition of a background K(+) conductance, which generates a receptor potential necessary for neurosecretion and activation of sensory pathways in the gill. This appears to be a fundamental mechanism of O(2) sensing that arose early in vertebrate evolution, and was adopted later in mammalian O(2) chemoreceptors.

Animals↗
PubMed2005

Taipoxin induces synaptic vesicle exocytosis and disrupts the interaction of synaptophysin I with VAMP2.

The application of the snake neurotoxin taipoxin to hippocampal neurons in culture induced Ca(2+)-dependent synaptic vesicle (SV) exocytosis, with swelling of nerve terminals and redistribution of SV proteins to the axolemma. Using digital imaging videomicroscopy to measure fluorescence resonance energy transfer in live neurons, we also found that taipoxin modulates the machinery for neurosecretion by causing dissociation of the SV proteins synaptobrevin 2 and synaptophysin I at a stage preceding taipoxin-induced facilitation of SV fusion. These early effects of the toxin are followed by severe impairment of SV exo-endocytosis, which might underlie the prevention of neurotransmitter release reported after intoxication by taipoxin.

Animals↗
PubMed2003

Extra- and intracellular sphingosylphosphorylcholine promote spontaneous transmitter release from frog motor nerve endings.

Similar to phosphatidylinositol bisphosphate, sphingomyelin breakdown generates several lipids, including sphingosylphosphorylcholine (SPC), that are putative signaling molecules. The present study was undertaken to evaluate the involvement of SPC in transmitter release process. Intracellular recordings were made from isolated frog sciatic-sartorius nerve-muscle preparations, and the effects of SPC on neurosecretion in the form of miniature endplate potentials (MEPPs) were assessed. Extracellular application of SPC mixture (D,L-SPC) at 1, 10, and 25 microM increased the MEPP frequency by 68, 96, and 127%, respectively. D-erythro-SPC (dissolved in dimethyl sulfoxide but not coupled to bovine serum albumin), but not L-threo-SPC, was active extracellular; the former (at 10 microM) increased the MEPP frequency by 143%. D-erythro-SPC treatment did not significantly change the median amplitude or frequency-distribution of MEPPs. Intracellular delivery via liposomes, in which 10, 100, or 1000 microM SPC mixture was entrapped in liposomal aqueous phase, induced a concentration-dependent increase in MEPP frequency of 45, 91, and 100%, respectively. D-erythro-SPC and L-threo-SPC at the concentration of 100 microM increased the MEPP frequency by 117 and 67%, respectively, or 91 and 61%, respectively, when coupled to bovine serum albumin. Pretreatment with thapsigargin significantly reduced but did not abolish the effects of extracellular D-erythro-SPC (10 microM) or liposomes containing 100 microM D-erythro-SPC. Liposomes filled with 100 microM D-myo-inositol 1,4,5-trisphosphate (IP3) enhanced the MEPP frequency to the same magnitude as 100 microM D-erythro-SPC entrapped in liposomes. However, administration of 100 microM D-erythro-SPC and IP3 entrapped in the same liposomes enhanced the MEPP frequency by 70%, which was less than that produced by these two compounds alone. The result provides the first electrophysiological evidence that SPC can modulate transmitter release by an extra- or intracellular action at the frog motor nerve ending.

Animals↗
PubMed1972

Crustacean color-change hormone: amino acid sequence and chemical synthesis.

The blanching hormone of the prawn, Pandalus borealis, is pGlu-Leu-Asn-Phe-Ser-Pro-Gly-Trp-NH(2). Its structure was settled by a combination of mass spectrometry and Edman-dansyl analysis of a thermolysin fragment. Confirmation of the structure was obtained by chemical synthesis from amino acids. This neurosecreted hormone is active in picogram amounts when tested in shrimps.

Amino Acid Sequence↗
PubMed1990

Glucose, sulfonylureas, and neurotransmitter release: role of ATP-sensitive K+ channels.

Sulfonylurea-sensitive adenosine triphosphate (ATP)-regulated potassium (KATP) channels are present in brain cells and play a role in neurosecretion at nerve terminals. KATP channels in substantia nigra, a brain region that shows high sulfonylurea binding, are inactivated by high glucose concentrations and by antidiabetic sulfonylureas and are activated by ATP depletion and anoxia. KATP channel inhibition leads to activation of gamma-aminobutyric acid (GABA) release, whereas KATP channel activation leads to inhibition of GABA release. These channels may be involved in the response of the brain to hyper- and hypoglycemia (in diabetes) and ischemia or anoxia.

Adenosine Triphosphate↗
PubMed1978

Immunoreactive vasopressin and oxytocin: concentration in individual human hypothalamic nuclei.

Individual hypothalamic nuclei were microdissected from brain tissue of ten human subjects who had died suddenly while in apparent good health. Appreciable amounts of vasopressin and oxytocin immunoreactivity were found by specific radioimmunoassay in six hypothalamic nuclei including supraoptic and paraventricular nuclei. Vasopressin and oxytocin are presumed to be synthesized in supraoptic and paraventricular nuclei for axonal transport to the posterior pituitary for storage and release. Vasopressin and oxytocin in other hypothalamic nuclei may be a part of this system of neurosecretion or may serve some other function.

Adolescent↗
PubMed1984

Growth hormone-releasing factor: direct effects on growth hormone, glucose, and behavior via the brain.

Intracerebroventricular administration of human pancreatic growth hormone-releasing factor caused a dose-dependent inhibition of growth hormone secretion, elevated plasma glucose concentrations, and produced marked behavioral and motor effects. Immunoneutralization with antiserum to somatostatin did not reverse the suppression of growth hormone. These findings suggest that hypothalamic growth hormone-releasing factor may regulate its own neurosecretion through an "ultrashort-loop" negative feedback mechanism and may have important neurotransmitter and neuromodulatory functions in the brain.

Animals↗
PubMed1995

Other lipopeptides.

Several authors' changes should have been included in the response by D. B. Wheeler et al. to the technical comment "Identification of calcium channels that control neurosecretion" (4 Nov., p. 830). A sentence reading, "Comparisons with experiments using higher concentrations of carrier protein (1.0 mg/mL) revealed no significant differences in the rate of efficacy of omega-Aga-IVA action" should have been inserted before the last sentence in the legend of figure 1. The measure "30 nM" (not 20 nM) should have appeared 19 lines from the bottom of the last column on page 830. The second-to-last sentence in that paragraph should read, "Increasing the duration of exposure to 30 nM omega-Aga-IVA from 20 min (1) to 45 min revealed significant inhibition of synaptic transmission (n = 9)." Reference "(15)" (not 16) should have appeared seven lines from the top of the first column on page 831.

Aspartic Acid↗
PubMed2002

Ral-GTPase influences the regulation of the readily releasable pool of synaptic vesicles.

The Ral proteins are members of the Ras superfamily of GTPases. Because they reside in synaptic vesicles, we used transgenic mice expressing a dominant inhibitory form of Ral to investigate the role of Ral in neurosecretion. Using a synaptosomal secretion assay, we found that while K(+)-evoked secretion of glutamate was normal, protein kinase C-mediated enhancement of glutamate secretion was suppressed in the mutant mice. Since protein kinase C effects on secretion have been shown to be due to enhancement of the size of the readily releasable pool of synaptic vesicles docked at the plasma membrane, we directly measured the refilling of this readily releasable pool of synaptic vesicles after Ca(2+)-triggered exocytosis. Refilling of the readily releasable pool was suppressed in synaptosomes from mice expressing dominant inhibitory Ral. Moreover, we found that protein kinase C and calcium-induced phosphorylation of proteins thought to influence synaptic vesicle function, such as MARCKS, synapsin, and SNAP-25, were all reduced in synaptosomes from these transgenic mice. Concomitant with these studies, we searched for new functions of Ral by detecting proteins that specifically bind to it in cells. Consistent with the phenotype of the transgenic mice described above, we found that active but not inactive RalA binds to the Sec6/8 (exocyst) complex, whose yeast counterpart is essential for targeting exocytic vesicles to specific docking sites on the plasma membrane. These findings demonstrate a role for Ral-GTPase signaling in the modulation of the readily releasable pool of synaptic vesicles and suggest the possible involvement of Ral-Sec6/8 (exocyst) binding in modulation of synaptic strength.

Animals↗