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PubMed2006

Ryanodine receptor interaction with the SNARE-associated protein snapin.

The ryanodine receptor (RyR) is a widely expressed intracellular calcium (Ca(2+))-release channel regulating processes such as muscle contraction and neurotransmission. Snapin, a ubiquitously expressed SNARE-associated protein, has been implicated in neurotransmission. Here, we report the identification of snapin as a novel RyR2-interacting protein. Snapin binds to a 170-residue predicted ryanodine receptor cytosolic loop (RyR2 residues 4596-4765), containing a hydrophobic segment required for snapin interaction. Ryanodine receptor binding of snapin is not isoform specific and is conserved in homologous RyR1 and RyR3 fragments. Consistent with peptide fragment studies, snapin interacts with the native ryanodine receptor from skeletal muscle, heart and brain. The snapin-RyR1 association appears to sensitise the channel to Ca(2+) activation in [(3)H]ryanodine-binding studies. Deletion analysis indicates that the ryanodine receptor interacts with the snapin C-terminus, the same region as the SNAP25-binding site. Competition experiments with native ryanodine receptor and SNAP25 suggest that these two proteins share an overlapping binding site on snapin. Thus, regulation of the association between ryanodine receptor and snapin might constitute part of the elusive molecular mechanism by which ryanodine-sensitive Ca(2+) stores modulate neurosecretion.

Animals↗
PubMed1994

CALCIUM CHANNEL CURRENTS IN CULTURED PARS INTERCEREBRALIS NEUROSECRETORY CELLS OF ADULT LOCUSTA MIGRATORIA

The medial neurosecretory cells (MNSCs) of the pars intercerebralis in the brain of insects release various hormonal factors that control essential physiological and developmental functions such as moulting, reproduction and metabolism (Wigglesworth, 1940; Girardie, 1966; Goldsworthy, 1969), and these cells are therefore of considerable biological significance. A culture system for locust embryonic pars intercerebralis neurosecretory cells has recently been developed (Vanhems et al. 1993), and Rossler and Bickmeyer (1993) have established an in vitro system for growing larval and adult medial neurosecretory cells. Calcium plays an important role in neural physiology: neurosecretion depends on calcium influx into the cells and calcium currents carry the rising phase of action potentials in different types of insect neurones (Orchard, 1976; Pitman, 1979); calcium also mediates other ionic currents (Thomas, 1984). It is therefore of considerable interest to characterize the types of calcium channel currents found in locust neurosecretory neurones.

Journal Article↗
PubMed2003

Neuropeptide Y: a physiological orexigen modulated by the feedback action of ghrelin and leptin.

Neuropeptide Y (NPY), a 36-amino-acid neuropeptide is the most potent physiological appetite transducer known. Episodic NPY neurosecretion in hypothalamic target sites is temporally linked with onset of the daily feeding pattern. Upregulation of NPY signaling in the arcuate nucleus-paraventricular nucleus (ARC-PVN) neural axis is responsible for the hyperphagia evoked by dieting, fasting, hormonal and genetic factors, and disruption in intrahypothalamic signaling. Clusters of NPY-producing neurons in the ARC that coexpress gamma- amino butyric acid and agouti-related peptide, and those in the brain stem (BS) that coexpress catecholamines and galanin, participate in disparate manners to regulate appetitive behavior. NPY receptors, Y1, Y2, and Y5, expressed by various components of the NPY network, mediate NPY-induced feeding. Imbalance in NPY signaling due either to high or low abundance of NPY at target sites elicits hyperphagia leading to increased fat accretion and obesity. Recent studies show that intermittent, feedback action of opposing afferent hormonal signals-leptin from adipose tissue and ghrelin from stomach-regulate the episodic secretion of orexigenic NPY in the PVN-ARC. Apparently, the hypothalamic NPY network is the primary common pathway intimately involved in genesis of appetite- stimulating impulses.

Animals↗
PubMed2006

Dysregulation of brain-derived neurotrophic factor expression and neurosecretory function in Mecp2 null mice.

Disruptions in brain-derived neurotrophic factor (BDNF) expression are proposed to contribute to the molecular pathogenesis of Rett syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in methyl-CpG-binding protein-2 (MeCP2). Although MeCP2 is a transcriptional regulator of BDNF, it is unknown how MeCP2 mutations affect transsynaptic BDNF signaling. Our findings demonstrate an early, abnormal neurosecretory phenotype in MeCP2-deficient neurons characterized by significant increases in the percentage of cellular BDNF content available for release. However, loss of MeCP2 also results in deficits in total cell BDNF content that are developmentally regulated in a cell-type-specific manner. Thus, the net effect of MeCP2 loss on absolute BDNF secretion changes with age and is determined by both the amount of BDNF available for release and progressive declines in total cellular BDNF. We propose, therefore, that loss of MeCP2 function disrupts transsynaptic BDNF signaling by perturbing the normal balance between BDNF protein levels and secretion. However, mutant neurons are capable of secreting wild-type levels of BDNF in response to high-frequency electrical stimulation. In addition, we found elevated exocytic function in Mecp2(-/y) adrenal chromaffin cells, indicating that the Mecp2 null mutation is associated with alterations of neurosecretion that are not restricted to BDNF. These findings are the first examples of abnormal neuropeptide and catecholamine secretion in a mouse model of RTT.

Adrenal Glands↗
PubMed2005

Brain-derived neurotrophic factor enhances GABA release probability and nonuniform distribution of N- and P/Q-type channels on release sites of hippocampal inhibitory synapses.

Long-lasting exposures to brain-derived neurotrophic factor (BDNF) accelerate the functional maturation of GABAergic transmission in embryonic hippocampal neurons, but the molecular bases of this phenomenon are still debated. Evidence in favor of a postsynaptic site of action has been accumulated, but most of the data support a presynaptic site effect. A crucial issue is whether the enhancement of evoked IPSCs (eIPSCs) induced by BDNF is attributable to an increase in any of the elementary parameters controlling neurosecretion, namely the probability of release, the number of release sites, the readily releasable pool (RRP), and the quantal size. Here, using peak-scaled variance analysis of miniature IPSCs, multiple probability fluctuation analysis, and cumulative amplitude analysis of action potential-evoked postsynaptic currents, we show that BDNF increases release probability and vesicle replenishment with little or no effect on the quantal size, the number of release sites, the RRP, and the Ca2+ dependence of eIPSCs. BDNF treatment changes markedly the distribution of Ca2+ channels controlling neurotransmitter release. It enhances markedly the contribution of N- and P/Q-type channels, which summed to >100% ("supra-additivity"), and deletes the contribution of R-type channels. BDNF accelerates the switch of presynaptic Ca2+ channel distribution from "segregated" to "nonuniform" distribution. This maturation effect was accompanied by an uncovered increased control of N-type channels on paired-pulse depression, otherwise dominated by P/Q-type channels in untreated neurons. Nevertheless, BDNF preserved the fast recovery from depression associated with N-type channels. These novel presynaptic BDNF actions derive mostly from an enhanced overlapping and better colocalization of N- and P/Q-type channels to vesicle release sites.

Analysis of Variance↗
PubMed2006

Neuroendocrine control of reproductive aging: roles of GnRH neurons.

The process of reproductive senescence in many female mammals, including humans, is characterized by a gradual transition from regular reproductive cycles to irregular cycles to eventual acyclicity, and ultimately a loss of fertility. In the present review, the role of the hypothalamic gonadotropin-releasing hormone (GnRH) neurons is considered in this context. GnRH neurons provide the primary driving force upon the other levels of the reproductive axis. With respect to aging, GnRH cells undergo changes in biosynthesis, processing and release of the GnRH decapeptide. GnRH neurons also exhibit morphologic and ultrastructural alterations that appear to underlie these biosynthetic properties. Thus, functional and morphologic changes in the GnRH neurosecretory system may play causal roles in the transition to acyclicity. In addition, GnRH neurons are regulated by numerous inputs from neurotransmitters, neuromodulators and glia. The relationship among GnRH cells and their inputs at the cell body (thereby affecting GnRH biosynthesis) and the neuroterminal (thereby affecting GnRH neurosecretion) is crucial to the function of the GnRH system, with age-related changes in these relationships contributing to the reproductive senescent process. Therefore, the aging hypothalamus is characterized by changes intrinsic to the GnRH cell, as well as its regulatory inputs, which summate to contribute to a loss of reproductive competence in aging females.

Adult↗
PubMed1987

Effects of calmodulin antagonists on norepinephrine release and vascular responsiveness in rat mesenteric vasculature.

This study was designed to investigate the role of calmodulin in adrenergic neurotransmission of resistance vessels. The effects of various calmodulin antagonists (trifluoperazine, W-7, calmidazolium, chlorpromazine, fluphenazine) on the vascular responsiveness and norepinephrine overflow from adrenergic nerve endings were examined in perfused rat mesenteric vasculature preparations. Pressor responses to electrical nerve stimulation or exogenous norepinephrine were inhibited dose-dependently by each calmodulin antagonist. Norepinephrine overflow from the sympathetic nerve endings during electrical nerve stimulation was also suppressed by calmodulin antagonists. These results indicate that calmodulin antagonists affected both pre- and post-synaptic sites of adrenergic neurotransmission, suggesting that calmodulin is involved both in neurosecretion and vascular smooth muscle contractions in peripheral resistance vessels.

Animals↗
PubMed1999

Clusterin is expressed in the anterior and intermediate lobes, but not in the posterior pituitary of sheep.

We have examined the expression of the ovine clusterin gene in the sheep pituitary gland, with the aim of determining its site of synthesis in this tissue. Northern blotting analysis of extracted polyadenylated RNA, using a (32)P-labelled rat clusterin cDNA probe, detected the greatest amounts of clusterin mRNA in the anterior part of dissected pituitary glands. In situ hybridisation studies showed clusterin mRNA in anterior and intermediate pituitary cells, with lower amounts in vascular endothelium and posterior pituicytes. Clusterin protein, detected by immunohistochemistry, was observed in some single secretory cells, within the capillary lumen and in cells around capillaries in the anterior and intermediate lobes, but no immunoreactivity was observed in posterior pituitary tissue. The pattern of clusterin expression in anterior and intermediate pituitary cells suggests possible roles for the protein in secretory cell turnover and/or hormone secretion or lipid uptake. Clusterin does not appear to be involved in ovine posterior pituitary hormone neurosecretion.

Animals↗
PubMed1975

Release of corticotrophin releasing factor and other hypophysiotropic substances from isolated nerve-endings (synaptosomes).

Synaptosomes isolated from the sheep and the rat hypothalamus contain corticotrophin releasing factor, vasopressin, prolactin-release inhibiting factor and probably all of the substances which participate in the regulation of adenohypophysial function. Electrical field stimulation or depolarizing concentrations (55 mmol/l) of potassium ions cause a release of these factors from the incubated nerve-endings in a calcium-dependent manner. It is suggested that synaptosomes may provide a valuable approach to the study of mechanisms involved in hypothalamic neurosecretion in vitro.

Adrenocorticotropic Hormone↗
PubMed2005

Endocrine roles of D-aspartic acid in the testis of lizard Podarcis s. sicula.

In the lizard Podarcis s. sicula, a substantial amount of D-aspartate (D-Asp) is endogenous to the testis and shows cyclic changes of activity connected with sex hormone profiles during the annual reproductive phases. Testicular D-Asp content shows a direct correlation with testosterone titres and a reverse correlation with 17beta-estradiol titres. In vivo experiments, consisting of i.p. injections of 2.0 micromol/g body weight of D-Asp or other amino acids, in lizards collected during the three main phases of the reproductive cycle (pre-reproductive, reproductive and post-reproductive period), revealed that the testis can specifically take up and accumulate D-Asp alone. Moreover, this amino acid influences the synthesis of testosterone and 17beta-estradiol in all phases of the cycle. This phenomenon is particularly evident during the pre- and post-reproductive period, when endogenous testosterone levels observed in both testis and plasma were the lowest and 17beta-estradiol concentrations were the highest. D-Asp rapidly induces a fall in 17beta-estradiol and a rise in testosterone at 3 h post-injection in the testis and at 6 h post-injection in the blood. In vitro experiments show that testicular tissue converted L-Asp into D-Asp through an aspartate racemase. D-Asp synthesis was measured in all phases of the cycle, but was significantly higher during the reproductive period with a peak at pH 6.0. The exogenous D-Asp also induces a significant increase in the mitotic activity of the testis at 3 h (P < 0.05) and at 6 h (P < 0.01). Induction of spermatogenesis by D-Asp is recognized by an intense immunoreactivity of the germinal epithelium (spermatogonia and spermatids) for proliferation cell nuclear antigen (PCNA). The effects of D-Asp on the testis appear to be specific since they were not seen in lizards injected with other D- or L-forms of amino acids with known excitatory effects on neurosecretion. Our results suggest a regulatory role for D-Asp in the steroido-genesis and spermatogenesis of the testis of the lizard Podarcis s. sicula.

Amino Acid Isomerases↗
PubMed1982

Fine structure of Duvernoy's gland of the Japanese colubrid snake, Rhabdophis tigrinus.

Duvernoy's gland (a type of venom gland) of the Japanese colubrid snake, Rhabdophis tigrinus, was examined by electron microscopy. The secretory units of the gland consist of the secretory and myoepithelial cells. The secretory cells are columnar in shape and have well-developed rough endoplasmic reticulum (RER), Golgi apparatus and mitochondria in the basal perinuclear cytoplasm. The secretory granules are homogeneous in structure and moderately dense. They are accumulated in the apical cytoplasm and are released by exocytosis into the lumen. The myoepithelial cells often enclose the secretory units, contain bundles of filaments in the cytoplasmic process, and are innervated by the free endings of the autonomic nerves through the basement membrane. In addition, many nerve terminals end in pericapillary spaces, suggesting a release of neurosecretions into the blood. The duct epithelium is composed of typical mucus secreting cells, whose cytoplasm contains secretory globules of lower electron density.

Animals↗
PubMed1989

Morphological aspects of neurons as secretory cells.

The concept of a neurosecretory system consisting of a secretory center (production of bioactive substances in neuronal soma), a transport pathway (transport by axonal flow) and a neurohemal organ (storage and release at nerve endings) has been established through a series of histological studies on the hypothalamic magnocellular nuclei by two pioneers, Scharrer and Bargmann, together with their co-workers. In the early stages of the investigation, these actively secreting neurons were considered as exceptional neurons, separated from ordinary ones. However, since the application of modern techniques, such as electron microscopy, immunohistochemistry, and in situ hybridization, have made progress in tracing the cytological course from the gene expression to the release of bioactive product, it has become obvious that the classical definition of neurosecretion must be extended to include a variety of neuroepithelial derivatives, such as aminergic and peptidergic neurons and also paraneurons. At present, all neurotransmitters and neuro-modulators can be regarded as secretory substances produced in neurons. Newly developed precise techniques, e.g., a tracing method with a computer graphic system for the demonstration of axonal arborizations, have led to a dramatic change in our understanding of the fine details of cytological features, offering much more complicated structures than images presented by the classical impregnation technique. Immunohistochemically demonstrated serotoninergic neurons in the brain have revealed enormous reticular extensions and anastomoses of beaded processes which were previously unknown. Neurons composing the nervous system show greatly varied shapes and structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Ultrastructural simultaneous localization of vasoactive intestinal polypeptide immunoreactivity and the acetylcholine-like cation in rat endocrine pancreas.

The ultrastructural co-localization of vasoactive intestinal polypeptide (VIP) and acetylcholine (ACh)-like cation was demonstrated in the rat endocrine pancreas. Immunoperoxidase cytochemical procedure for the detection of VIP was followed by ionic fixation of ACh by silicotungstic acid. All the VIP-immunoreactive nerve endings displayed punctiform precipitates revealing ACh-like cations in the small clear vesicles. Almost all the VIP-immunoreactive nerve terminals were in contact with endocrine A, B or D cells, but not in the close vicinity of blood vessels. Nerve endings devoid of VIP immunoreactivity but containing ACh-like cations were seen either in contact with endocrine cells or in close vicinity to blood vessels. These data suggest that VIP might modulate, concomitantly with ACh, the hormonal secretion of the endocrine pancreas, although the possibility of the neurosecretion of ACh and VIP into the blood vessels should not be excluded. ACh might also control some function of the endothelial cells of blood vessels.

Acetylcholine↗
PubMed1996

Dark neurons in the mouse brain: an investigation into the possible significance of their variable appearance within a day and their relation to negatively charged cell coats.

This study aims to investigate the occurrence and nature of dark neurons in the central nervous system under physiological conditions. Mouse brain tissues were perfusion-fixed with paraformaldehyde or glutaraldehyde at 4 h intervals during one day (3:00, 7:00, 11:00, 15:00, 19:00, 23:00). Paraffin sections were stained with the cationic colloidal iron method, and counterstained with nuclear fast red or carbolthionin. The dark neurons were readily distinguishable as their shrunken cell bodies stained densely with nuclear fast red or thionin. Some of the dark cells were coated with perineuronal sulfated proteoglycans; this coat, which formed a smoothly extended meshwork in light cells, presented spicule-like forms in the dark cells. The occurrence of dark cells in the retrosplenial cortex varied by the time of day: the incidence of the dark neurons was low (10-15%) at 11:00, 15:00 and 23:00, while it was significantly high (50-60%) at 3:00 and 19:00. Previous authors have ascribed the occurrence of dark neurons either to artifacts due to inappropriate fixation or to pathological damage. However, the present study strongly suggests that this type of neuron occurs under physiological conditions as reversible changes, and vary over a day, showing distinct peaks. These peaks occurred coincidentally while the mice were awake. Such morphological changes may be involved in the neuronal activation and exhaustion. Our view is consistent with the hypothesis (Tewari and Bourne, 1963) that the neurons take such dark profiles at certain stages of neurosecretion.

Animals↗
PubMed1979

Proposal of a a neurosecretory system in the pancreas. An electron microscope study in the dog.

The nerve fibers supplying the islets of the dog pancreas were examined by electron microscopy. Axons with swollen portions containing various types of synaptic vesicles, including a cholinergic type, two varieties of presumable aminergic type and a possible peptidergic type, rush to the pericapillary space to end there, whereas only a small part of them seem to terminate on the endocrine cells of the islet. Schwann cell cytoplasm invests the axons and often separates these from the endocrine cells. The terminal portions filled with vesicles usually become free of the Schwann sheath on the side facing the blood capillary. Here the neuronal secretions are believed to be released into the blood stream through the pored endothelium of the capillary. The neurosecretions, together with the islet hormones are distributed to the exocrine pancreas in high concentrations via the insulo-acinar portal system. It seems thus sufficient for the nerves to supply the islet in order to control the exocrine function of the pancreas.

Animals↗
PubMed2001

Experimental uremia affects hypothalamic amino acid neurotransmitter milieu.

Chronic renal failure is associated with delayed puberty and hypogonadism. To investigate the mechanisms subserving the reported reduced pulsatile release of gonadotropin-releasing hormone (GnRH) in chronic renal failure, this study examined the amino acid neurotransmitter milieu in the medial preoptic area (MPOA), the hypothalamic region where the GnRH-secreting neurons reside, in 5/6-nephrectomized male rats and in ad libitum-fed or pair-fed controls. All rats were castrated and received either a testosterone or a vehicle implant to evaluate additional effects of the prevailing sex steroid milieu. Local excitatory (essential amino acids: aspartate, glutamate) and inhibitory (gamma-aminobutyric acid [GABA], taurine) amino acid transmitter outflow in the MPOA was measured by microdialysis via stereotactically implanted cannulae in the awake, freely moving rats. In addition to basal extracellular concentrations, the neurosecretory capacity was assessed by the addition of 100 mM KCl to the dialysis fluid. The mechanisms of neurosecretion were evaluated further by inhibition of vesicular release with the use of Ca(2+)-free, Mg(2+)-enriched dialysis fluid and by local perfusion with inhibitors of voltage-dependent synaptic release (1 microM tetrodotoxin) and of GABA reuptake (0.5 mM nipecotic acid). In the uremic rats, basal outflow of GABA, glutamate and aspartate, and K(+)-stimulated aspartate outflow were increased. K(+)-stimulated GABA and glutamate release was less sensitive to Ca(2+) depletion in the uremic than in the control rats. The elevated basal GABA and essential amino acid outflow in the uremic rats was due to a voltage- and Ca(2+)-independent mechanism. GABA reuptake was inhibited proportionately by nipecotic acid in uremic and pair-fed control rats. Testosterone supplementation had no independent effects on neurotransmitter outflow. In summary, the amino acid neurotransmitter milieu is altered in the MPOA of uremic rats by a nonsynaptic, nonvesicular mechanism. These abnormalities may contribute to the impaired function of the GnRH pulse generator.

Amino Acids↗
PubMed1987

The modulation of visceral functions by somatic afferent activity.

We began by briefly reviewing the historical background of neurophysiological studies of the somato-autonomic reflexes and then discussed recent studies on somatic-visceral reflexes in combination with autonomic efferent nerve activity and effector organ responses. Most of the studies that have advanced our knowledge in this area have been carried out on anesthetized animals, thus eliminating emotional factors. We would like to emphasize again that the functions of many, or perhaps all visceral organs can be modulated by somato-sympathetic or somato-parasympathetic reflex activity induced by a appropriate somatic afferent stimulation in anesthetized animals. As mentioned previously, some autonomic nervous outflow, e.g. the adrenal sympathetic nerve activity, is involved in the control of hormonal secretion. John F. Fulton wrote in his famous textbook "Physiology of the Nervous System" (1949) that the posterior pituitary neurosecretion system (i.e. for oxytocin and vasopressin) could be considered a part of the parasympathetic nervous system. In the study of body homeostasis and environmental adaptation it would seem very important to further analyze the contribution of somatic afferent input to the autonomic nervous and hormonal regulation of visceral organ activity. Also, some immunological functions have been found to be influenced by autonomic nerves or hormones (e.g. adrenal cortical hormone and catecholamines). Finally, we must take into account, as we have briefly discussed, that visceral functions can be modulated by somatic afferent input via various degrees of integration of autonomic nerves, hormones, and immunological processes. We trust that such research will be expanded to higher species of mammals, and that ultimately this knowledge of somato-visceral reflexes obtained in the physiological laboratory will become clinically useful in influencing visceral functions.

Afferent Pathways↗
PubMed2002

PACAP and its receptors exert pleiotropic effects in the nervous system by activating multiple signaling pathways.

Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally isolated from the ovine brain in 1989 as a novel hypothalamic hormone that potently activates adenylate cyclase to produce cyclic AMP in pituitary cells. This neuropeptide belongs to the secretin/glucagon/vasoactive intestinal peptide (VIP) superfamily, and exists in two amidated forms as PACAP38 (38-amino acid residues) and PACAP27 derived from the same precursor. The primary structure of PACAP has been remarkably conserved throughout evolution among tunicata, ichthyopsida, amphibia and mammalia, and a PACAP-like neuropeptide has also been determined in Drosophila. Both PACAP and its receptors are mainly distributed in the nervous and endocrine systems showing pleiotropic functions with high potency. There are three types of receptors with high PACAP-binding affinity and with different tissue-distribution patterns. All of them belong to G-protein-coupled receptor superfamily with seven transmembrane domains. PAC(1) is the PACAP-specific receptor and exists in at least eight splice variants which couple to different intracellular signal transduction pathways. VPAC(1) and VPAC(2) are the common receptors for both PACAP and VIP, which are coupled to adenylate cyclase. This review article presents and discusses an update on PACAP research and its pleiotropic physiological functions based on multiple receptor-mediated signaling mechanisms in both the central and peripheral nervous system, including the regulation of hypothalamic neurosecretion, homeostatic control of circadian clock and behavioral actions, involvement in learning and memory processes, neuroprotective effects such as anti-apoptosis and response to injury and inflammation, and neural ontogenetic functions on proliferation/differentiation processes from early stages.

Animals↗