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At least 883 records · Page 49Linked to original sources
PubMed2003

Identification and characterization of Snapin as a ubiquitously expressed SNARE-binding protein that interacts with SNAP23 in non-neuronal cells.

Members of the SNARE (soluble N -ethylmaleimide-sensitive fusion protein attachment protein receptor) superfamily [syntaxins, VAMPs (vesicle-associated membrane proteins) and SNAP25 (synaptosome-associated protein-25)-related proteins] are required for intracellular membrane-fusion events in eukaryotes. In neurons, assembly of SNARE core complexes comprising the presynaptic membrane-associated SNAREs syntaxin 1 and SNAP25, and the vesicle-associated SNARE VAMP2, is necessary for synaptic vesicle exocytosis. Several accessory factors have been described that associate with the synaptic SNAREs and modulate core complex assembly or mediate Ca2+ regulation. One such factor, Snapin, has been reported to be a brain-specific protein that interacts with SNAP25, and regulates association of the putative Ca2+-sensor synaptotagmin with the synaptic SNARE complex [Ilardi, Mochida and Sheng (1999) Nat. Neurosci. 2, 119-124]. Here we demonstrate that Snapin is expressed ubiquitously in neuronal and non-neuronal cells. Furthermore, using protein-protein-interaction assays we show that Snapin interacts with SNAP23, the widely expressed homologue of SNAP25, and that the predicted C-terminal helical domain of Snapin contains the SNAP23-binding site. Subcellular localization experiments revealed that Snapin is a soluble protein that exists in both cytosolic and peripheral membrane-bound pools in adipocytes. Moreover, association of Snapin with the plasma membrane was detected in cells overexpressing a Snapin-green fluorescent protein fusion protein. Finally, we show that Snapin is able to form a ternary complex with SNAP23 and syntaxin 4, suggesting that it is a component of non-neuronal SNARE complexes. An important implication of our results is that Snapin is likely to perform a general role in SNARE-mediated vesicle fusion events in non-neuronal cells in addition to its participation in Ca2+-regulated neurosecretion.

3T3-L1 Cells↗
PubMed2003

Modulation of spontaneous transmitter release from the frog neuromuscular junction by interacting intracellular Ca(2+) stores: critical role for nicotinic acid-adenine dinucleotide phosphate (NAADP).

Nicotinic acid-adenine dinucleotide phosphate (NAADP) is a recently described potent intracellular Ca(2+)-mobilizing messenger active in a wide range of diverse cell types. In the present study, we have investigated the interaction of NAADP with other Ca(2+)-mobilizing messengers in the release of transmitter at the frog neuromuscular junction. We show, for the first time, that NAADP enhances neurosecretion in response to inositol 1,4,5-trisphosphate (IP(3)), cADP-ribose (cADPR) and sphingosine 1-phosphate (S1P), but not sphingosylphosphorylcholine. Thapsigargin was without effect on transmitter release in response to NAADP, but blocked the responses to subsequent application of IP(3), cADPR and S1P and their potentiation by NAADP. Asynchronous neurotransmitter release may therefore involve functional coupling of endoplasmic reticulum Ca(2+) stores with distinct Ca(2+) stores targeted by NAADP.

Animals↗
PubMed2003

Identification of SNARE complex modulators that inhibit exocytosis from an alpha-helix-constrained combinatorial library.

Synthetic peptides patterned after the proteins involved in vesicle fusion [the so-called SNARE (soluble N -ethylmaleimide-sensitive fusion protein attachment protein receptor) proteins] are potent inhibitors of SNARE complex assembly and neuronal exocytosis. It is noteworthy that the identification of peptide sequences not related to the SNARE proteins has not been accomplished yet; this is due, in part, to the structural constraints and the specificity of the protein interactions that govern the formation of the SNARE complex. Here we have addressed this question and used a combinatorial approach to identify peptides that modulate the assembly of the SNARE core complex and inhibit neuronal exocytosis. An alpha-helix-constrained, mixture-based, 17-mer combinatorial peptide library composed of 137180 sequences was synthesized in a positional scanning format. Peptide mixtures were assayed for their ability to prevent the formation of the in vitro -reconstituted SDS-resistant SNARE core complex. Library deconvolution identified eight peptides that inhibited the assembly of the SNARE core complex. Notably, the most potent 17-mer peptide (acetyl-SAAEAFAKLYAEAFAKG-NH2) abolished both Ca2+-evoked catecholamine secretion from detergent-permeabilized chromaffin cells and L-glutamate release from intact hippocampal primary cultures. Collectively, these findings indicate that amino acid sequences that prevent SNARE complex formation are not restricted to those that mimic domains of SNARE proteins, thus expanding the diversity of molecules that target neuronal exocytosis. Because of the implication of neurosecretion in the aetiology of several human neurological disorders, these newly identified peptides may be considered hits for the development of novel anti-spasmodic drugs.

Amino Acid Sequence↗
PubMed2001

Capsaicin-evoked CGRP release from rat buccal mucosa: development of a model system for studying trigeminal mechanisms of neurogenic inflammation.

Many of the physiological hallmarks associated with neurogenic inflammatory processes in cutaneous tissues are similarly present within orofacial structures. Such attributes include the dependence upon capsaicin-sensitive sensory neurons and the involvement of certain inflammatory mediators derived therein, including calcitonin gene-related peptide (CGRP). However, there are also important differences between the trigeminal and spinal nervous systems, and the potential contributions of neurogenic processes to inflammatory disease within the trigeminal system have yet to be fully elucidated. We present here a model system that affords the ability to study mechanisms regulating the efferent functions of peptidergic terminals that may subserve neurogenic inflammation within the oral cavity. Freshly dissected buccal mucosa tissue from adult, male, Sprague-Dawley rats was placed into chambers and superfused with oxygenated, Krebs buffer. Serial aliquots of the egressing superfusate were acquired and analysed by radioimmunoassay for immunoreactive CGRP (iCGRP). Addition of the selective excitotoxin, capsaicin (10-300 microm), to the superfusion buffer resulted in a significant, concentration-dependent increase in superfusate levels of iCGRP. Similarly, release of iCGRP from the buccal mucosa could also be evoked by a depolarizing concentration of potassium chloride (50 mm) or by the calcium ionophore A23187 (1 microm). The specific, capsaicin receptor antagonist, capsazepine (300 microm), completely abolished the capsaicin-evoked release of iCGRP while having no effect whatsoever on the potassium-evoked release. Moreover, capsaicin-evoked release was dependent upon the presence of extracellular calcium ions and was significantly, though incompletely, attenuated by neonatal capsaicin denervation. Collectively, these data indicate that the evoked neurosecretion of iCGRP in response to capsaicin occurs via a vanilloid receptor-mediated, exocytotic mechanism. The model system described here should greatly facilitate future investigations designed to identify and characterize the stimuli that regulate the release of CGRP or other neurosecretory substances in isolated tissues. This system may also be used to elucidate the role of these mediators in the aetiology of inflammatory processes within the trigeminal field of innervation.

Animals↗
PubMed1998

Prolonged hormone secretion from neuroendocrine cells of Aplysia is independent of extracellular calcium.

The role of Ca2+ from extracellular and intracellular sources in stimulating neurosecretion was investigated in four experiments using neuroendocrine bag cells of the marine mollusk Aplysia. (i) Bag cells were treated with either an extracellular calcium chelator (BAPTA) or Co(2+)-substitution within 30 s after onset of an electrical afterdischarge to prevent influx of Ca2+ from extracellular fluid. These treatments shortened the duration of the afterdischarge, but did not significantly affect the overall pattern or total amount of egg laying hormone (ELH) secretion, suggesting that extracellular Ca2+ is not required for maintenance of ELH release. (ii) Substitution of Ba2+ for Ca2+ has previously been shown to support bag cell afterdischarges that trigger transient elevations in intracellular Ca2+. We showed that this treatment also stimulates ELH secretion, suggesting that Ca2+ release from intracellular stores can stimulate ELH secretion. (iii) To raise intracellular Ca2+ levels in the absence of an afterdischarge, the calcium ionophore X537A was used to transport Ca2+ across plasma and organelle membranes. When this treatment was combined with extracellular calcium chelators so that the only source of Ca2+ was from intracellular compartments, ELH secretion was stimulated. Taken together, these findings are consistent with the hypothesis that release of Ca2+ from intracellular stores is sufficient to stimulate ELH secretion.

Animals↗
PubMed1999

The neurology and enterology of equine grass sickness: a review of basic mechanisms.

Autonomic dysfunction constitutes a prominent clinical feature of equine grass sickness (EGS). Significant injury to the nervous control of the alimentary system is life threatening, partly because of dysphagia but also because of the failure of the unique regulatory mechanisms in equine digestion involving water and electrolyte balance. The neuropathology also indicates the presence of a somatic polyneuropathy. The morphological features of EGS are similar to those of excitotoxic neuronal degeneration, which resembles neuronal apoptosis. It is difficult to ascertain from published accounts the degree of damage to central neurones: the distribution is well documented and selective but the proportion of damage is poorly quantified. If lesions involve a significant number of regulatory neurones they should produce functional deficits. Any clinical assessment of horses, especially those with chronic EGS, should include a thorough neurological examination. Although this will not necessarily improve the outcome of the case, it may enable the rational selection of animals with a reasonable prognosis for recovery which is partly determined by the extent of CNS lesions. The evidence supports the following pathogenesis. There is an initial lesion in the enteric nervous system of susceptible horses. In the acute form of EGS, massive enteric neuronal damage occurs first functionally, then structurally leading to generalized alimentary smooth muscle atony, enhanced secretions and altered fluid fluxes. Severe distension of the stomach and small intestines rapidly develops, which augments the intestinal ileus by intersegmental inhibitory reflexes and causes colic and dehydration. In subacute cases, failure of intestinal bicarbonate buffer together with alimentary stasis rapidly reduces caecal-colonic fermentation. Thus the osmolality of large intestinal digesta reduces and water travels out of the bowel along osmotic gradients. Water returns to the circulation, but is eventually lost in the gastric and small intestinal secretions. The observation that pathological lesions may not be seen in the prevertebral ganglia within the first few days of acute cases supports the view that a functional deficit precedes structural lesions which may be secondary to a retrograde degeneration. It is therefore possible to resolve the observations that less damage may be seen in prevertebral ganglia and elsewhere in peracute and acute cases with the more common finding that greater neuronal damage is present in acute than in chronic cases. These different observations are probably time dependent. Chronic EGS occurs when there is less initial enteric nerve damage which may lead to less secondary prevertebral ganglionic pathology, and more time for functional and structural compensatory mechanisms to develop. Denervation hypersensitivity develops at target sites both in the gut and in peripheral somatic nerves which may account, in part, for the clinical signs of patchy sweating and muscle tremors. Raised circulating adrenaline levels may also account for generalized sweating, may contribute to gastrointestinal atony and may affect pacemakers at the pelvic flexure. Many of the features of EGS make worthwhile the re-investigation of Clostridium botulinum Group III toxins, which are known to prevent vesicular exocytosis, stimulate neurosecretion, produce neuronal chromatolysis and inhibit neutrophil migration. Also, evidence from other species suggests that increased nitrergic neuronal activity can account for many of the clinical signs of EGS, namely dysphagia, generalized ileus, gastric dilatation, sweating, peripheral vasodilatation, tachycardia, salivary hypersecretion, muscle wastage and cachexia.

Animals↗
PubMed1994

Differences in the distribution of cytochrome b561 and synaptophysin in dog splenic nerve: a biochemical and immunocytochemical study.

Compared with neurons of the CNS, the organization of the peripheral adrenergic axon and nerve terminal is more complex because two types of neurotransmitter-containing vesicles, i.e., large (LDVs) and small dense-core vesicles, coexist with the axonal reticulum (AR) and the well-characterized small synaptic vesicles. The AR, which is still poorly examined, is assumed to play some role in neurosecretion. We have studied the subcellular localization of noradrenaline, cytochrome b561, and synaptophysin in control and ligated dog splenic nerve using both biochemical and ultrastructural approaches. Noradrenaline and cytochrome b561 coaccumulated proximal to a ligation, whereas distally only the latter was found. Despite a codistribution with noradrenaline at high densities in sucrose gradients, synaptophysin did not accumulate on either side of the ligation. At the ultrastructural level, cytochrome b561 immunoreactivity was found on LDVs and AR elements, both accumulating proximal to the ligation. Distally, the multivesicular bodies (MVBs), immunolabeled for cytochrome b561, account for the retrograde transport of LDVs and AR membranes retrieved at the nerve terminal. No synaptophysin immunoreactivity could be detected on LDVs, AR, or MVBs. The results obtained from the ligation experiments together with the ultrastructural data clearly illustrate that synaptophysin is absent from LDVs and AR elements in adrenergic axons.

Animals↗
PubMed1996

A novel transmembrane protein with epidermal growth factor and follistatin domains expressed in the hypothalamo-hypophysial axis of Xenopus laevis.

Through the use of a screening strategy designed to isolate novel cDNAs encoding proteins concerned with pituitary secretion in Xenopus laevis, we discovered clone X7365, which encodes a transmembrane protein with a signal peptide, two follistatin modules, a unique epidermal growth factor domain, and a short cytoplasmic region. RNA expression analyses indicated that the X7365 transcript is enriched in neuroendocrine tissues. Immunohistochemical studies demonstrated that, in addition to being expressed in the optic tectum and in astrocytes in the optic nerve, the X7365 protein is concentrated in a discrete population of hypothalamic magnocellular neurons. Axons projecting to the median eminence and the neurointermediate lobe of the pituitary were also immunopositive, suggesting that X7365 functions in the regulation of magnocellular neurosecretion.

Amphiregulin↗
PubMed2004

Small peptides patterned after the N-terminus domain of SNAP25 inhibit SNARE complex assembly and regulated exocytosis.

Synthetic peptides patterned after the C-terminus of synaptosomal associated protein of 25 kDa (SNAP25) efficiently abrogate regulated exocytosis. In contrast, the use of SNAP25 N-terminal-derived peptides to modulate SNAP receptors (SNARE) complex assembly and neurosecretion has not been explored. Here, we show that the N-terminus of SNAP25, specially the segment that encompasses 22Ala-44Ile, is essential for the formation of the SNARE complex. Peptides patterned after this protein domain are potent inhibitors of SNARE complex formation. The inhibitory activity correlated with their propensity to adopt an alpha-helical secondary structure. These peptides abrogated SNARE complex formation only when added previous to the onset of aggregate assembly. Analysis of the mechanism of action revealed that these peptides disrupted the binary complex formed by SNAP25 and syntaxin. The identified peptides inhibited Ca2+-dependent exocytosis from detergent-permeabilized excitable cells. Noteworthy, these amino acid sequences markedly protected intact hippocampal neurones against hypoglycaemia-induced, glutamate-mediated excitotoxicity with a potency that rivalled that displayed by botulinum neurotoxins. Our findings indicate that peptides patterned after the N-terminus of SNAP25 are potent inhibitors of SNARE complex formation and neuronal exocytosis. Because of their activity in intact neurones, these cell permeable peptides may be hits for antispasmodic and analgesic drug development.

Amino Acid Sequence↗
PubMed2002

Circulating inhibitor of gonadotropin releasing hormone secretion by hypothalamic neurons in uremia.

BACKGROUND: Previous studies have suggested a neuroendocrine defect underlying uremic hypogonadism, characterized by a reduced secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). METHODS: We studied the GnRH-producing GT1-7 cell line and the LH-producing LbetaT-2 pituitary cell line under uremic conditions to investigate whether substances circulating in uremic plasma directly affect hypothalamic or pituitary hormone secretion. The cells were incubated with serum from 5/6-nephrectomized or sham-nephrectomized castrated rats, respectively. Furthermore, GT1 cells were incubated with delipidated sera, serum subfractions separated by molecular weight, or several peptide hormones. Cellular viability, apoptosis rate and extracellular hormone degradation were assessed separately. GnRH and LH were measured by RIA in supernatants and cell lysates. GnRH gene expression was assessed by Northern blot. RESULTS: Uremic serum caused a reduction of extracellular GnRH concentration by 31%, whereas intracellular GnRH increased by 12%. This effect was independent of serum lipids and enzymatic GnRH degradation but was abolished by trypsin digestion. Cellular viability, apoptosis rates and GnRH gene expression did not differ between the two groups. The inhibitory activity was recovered from the high-molecular weight fraction, whereas the fraction <5 kD had stimulatory activity. In contrast, uremic serum did not affect LH secretion from LbetaT-2 cells, indicating that the hypoactivity of the hypothalamo-pituitary gonadotrope unit results from an inhibition at the hypothalamic rather than the pituitary level. CONCLUSIONS: Our results suggest that uremic serum contains macromolecular and hydrophilic peptide(s) able to specifically suppress the neurosecretion of GnRH from GT1-7 cells.

Animals↗
PubMed1996

gamma-Aminobutyric acid secretion from pancreatic neuroendocrine cells.

BACKGROUND & AIMS: Neuroendocrine cells and tumors derived therefrom contain hormone-storing large dense core vesicles and neuron-like small synaptic vesicle analogues with unknown function. The aim of this study was to characterize the small synaptic vesicle pathway in detail. METHODS: In human pancreatic neuroendocrine tumors and corresponding mammalian cell lines, the expression of key proteins if regulated secretion were detected by immunofluorescence microscopy. Using 3H-gamma-aminobutyric acid (GABA), uptake and release by small synaptic vesicle analogues were studied. RESULTS: Tumor tissues obtained from 14 patients expressed key proteins of neurosecretion such as synaptobrevin, syntaxins, and SNAP 25. These proteins were also found in the cell lines AR42J, BON, RIN, and INR. The cell lines specifically transported GABA by low-affinity plasma membrane transporter and showed an adenosine triphosphate-sensitive GABA uptake into an intracellular compartment. Stored GABA was released upon stimulation by regulated exocytosis. Electrophysiological analyses suggested that calcium-dependent secretion was mediated by activation of voltage-dependent calcium channels of mainly the L type, but also of the N and probably the T type. CONCLUSIONS: Small synaptic vesicle analogues in neuroendocrine cells and tumors can store and secrete GABA and probably other amino acid transmitters by regulated exocytosis comparable with neurons.

Adult↗
PubMed1986

[Diagnosis of hamartoma of the tuber cinereum].

Hamartomas of the tuber cinereum are tumour-like collections of normal tissue in abnormal location. They are benign lesions with slow or absent growth and without any tendency to neoplastic evolution. Due to their neurosecreting properties they usually cause precocious puberty. Further neuroendocrine disturbances, seizures, or psychoneurological symptoms may be associated in some cases. Cisternography and CT are the most conclusive radiologic procedures in all cases. The typical feature is a well circumscribed round-shaped isodense soft tissue mass without contrast enhancement. Usually the tumour is small, rarely exceeding 2 cm. in diameter. If CT diagnosis is not conclusive, examination in the coronal plane or CT cisternography are recommended. Although CT does not permit a histological diagnosis the clinical and radiological features together are sufficient to make a highly suggestive diagnosis. The treatment of choice is medical therapy. Surgery should be restricted to those tumours which damage surrounding structures by their size and cause other symptoms than precocious puberty.

Adolescent↗
PubMed1982

Neurotypy: regional individuality in rat brain detected by immunocytochemistry with monoclonal antibodies.

Hybridomas from spleen cell fusions of six BALB/c mice immunized with hypothalamus were analyzed by immunocytochemistry for antibodies reactive with paraffin sections of fixed rat brain. In a total of 135 antibody producers, 60% were brain specific. Among these, 54% reacted with glial elements, pituitary cells, or basal lamina of intracerebral capillaries, with little variation among individual hybridomas in each of these groups. Forty-six percent of brain-specific antibodies reacted with neuronal structures, localizing on nerve fibers, neurofibrils, or perikarya. Neuron-specific hybridomas could be classified into groups that localized in anatomically defineable overall patterns. Within these patterns individual hybridomas exhibited extensive qualitative localization diversity ("neurotypy"). Conceivably, the genetic message for a common "proantigen" within an overall pattern may be slightly modified during differentiation of a neuron, thus leading to minor variability in antigenic expression. During antibody formation, similar minor changes occur in the differentiation of the genetic message for the antibody variable region. Apparently, minor changes in the antibody combining site among groups of hybridomas is reflected in the detectability of minor neurotypic changes among differentiated neuronal proantigens. If neurotypy proves to be the result of single-base substitutions or of variability in alignment of peptide-coding exons, the Scharrer concept of the fundamental significance of neurosecretion could also become applicable to neuronal specialization.

Animals↗
PubMed1990

Calcium currents recorded from a vertebrate presynaptic nerve terminal are resistant to the dihydropyridine nifedipine.

The influx of Ca ions into the presynaptic nerve terminal through ion channels is a key link between the action potential and the release of chemical transmitters. It is not clear, however, which types of Ca channel are involved in neurosecretion at vertebrate synapses. In particular, there is disagreement as to whether these channels are sensitive to dihydropyridine blockers, characteristic of L-type Ca channels. We have used the chicken ciliary ganglion calyx synapse to test the effect of the dihydropyridine nifedipine on Ca current recorded directly from a cholinergic presynaptic nerve terminal. We used a control neuron to define the experimental conditions under which L-type Ca channels are blocked by 10 microM nifedipine. We then tested the effect of the dihydropyridine on Ca currents recorded from the presynaptic terminal using the same conditions. Nifedipine did not reduce the calyx Ca current nor did it block chemical transmission through the ganglion. The lack of effect of the dihydropyridine was not due to restricted access since omega-conotoxin GVIA, a peptide toxin that blocks transmission at this synapse, rapidly blocked the calyx Ca current. Thus, the predominant Ca channel in this presynaptic nerve terminal is not dihydropyridine sensitive and, hence, cannot be characterized as L-type.

Animals↗
PubMed1991

Receptors and neurosecretory actions of endothelin in hypothalamic neurons.

Primary cultures of rat hypothalamic neurons were found to secrete the potent calcium-mobilizing and mitogenic peptide endothelin (ET) and to contain specific ET binding sites with higher affinity for ET-1 and ET-2 than ET-3. ET receptors of similar specificity were also identified in two gonadotropin-releasing hormone (GnRH) neuronal cell lines (GT1-1 and GT1-7). In both primary cultures and GnRH neurons, receptor binding of ETs led to marked and dose-dependent increases of inositol phosphates; inositol bis-, tris-, and tetrakisphosphates increased promptly, reached a peak within 2 min, and returned toward the steady-state levels during the next 10 min. ET-1 was more potent than ET-3 in mobilizing inositol phosphates, consistent with its greater affinity for the ET receptors in these cells. ET also stimulated GnRH secretion from perifused hypothalamic cultures and GnRH cell lines, with a sharp increase followed by a prompt decline to the basal level. These data show that ET is produced in the hypothalamus and acts through calcium-mobilizing ET receptors in normal and transformed secretory neurons to stimulate GnRH release. These actions of locally produced ETs upon GnRH-secreting neurons indicate that the vasoconstrictor peptides have the capacity to regulate neurosecretion and could participate in the hypothalamic control of anterior pituitary function and gonadotropin secretion.

Animals↗
PubMed1993

Multiple Ca2+ channel types coexist to regulate synaptosomal neurotransmitter release.

The regulation of excitation-secretion coupling by Ca2+ channels is a fundamental property of the nerve terminal. Peptide toxins that block specific Ca2+ channel types have been used to identify which channels participate in neurotransmitter release. Subsecond measurements of [3H]-glutamate and [3H]dopamine release from rat striatal synaptosomes showed that P-type channels, which are sensitive to the Agelenopsis aperta venom peptide omega-Aga-IVA, trigger the release of both transmitters. Dopamine (but not glutamate) release was also controlled by N-type, omega-conotoxin-sensitive channels. With strong depolarizations, where neither toxin was very effective alone, a combination of omega-Aga-IVA and omega-conotoxin produced a synergistic inhibition of 60-80% of Ca(2+)-dependent dopamine release. The results suggest that multiple Ca2+ channel types coexist to regulate neurosecretion under normal physiological conditions in the majority of nerve terminals. P- and N-type channels coexist in dopaminergic terminals, while P-type and a omega-conotoxin- and omega-Aga-IVA-resistant channel coexist in glutamatergic terminals. Such an arrangement could lend a high degree of flexibility in the regulation of transmitter release under diverse conditions of stimulation and modulation.

Animals↗
PubMed1995

O2-sensitive K+ currents in carotid body chemoreceptor cells from normoxic and chronically hypoxic rats and their roles in hypoxic chemotransduction.

Carotid body-mediated ventilatory increases in response to acute hypoxia are attenuated in animals reared in an hypoxic environment. Normally, O2-sensitive K+ channels in neurosecretory type I carotid body cells are intimately involved in excitation of the intact organ by hypoxia. We have therefore studied K+ channels and their sensitivity to acute hypoxia (PO2 12-20 mmHg) in type I cells isolated from neonatal rats born and reared in normoxic and hypoxic environments. When compared with cells from normoxic rats, K+ current density in cells from hypoxic rats was significantly reduced, whereas Ca2+ current density was unaffected. Charybdotoxin (20 nM) inhibited K+ currents in cells from normoxic rats by approximately 25% but was without significant effect in cells from hypoxic rats. However, hypoxia caused similar, reversible inhibitions of K+ currents in cells from the two groups. Resting membrane potentials (measured at 37 degrees C using the perforated-patch technique) were similar in normoxic and hypoxic rats. However, although acute hypoxia depolarized type I cells of normoxic rats, it was without effect on membrane potential in type I cells from hypoxic animals. Charybdotoxin (20 nM) also depolarized cells from normoxic rats. Our results suggest that type I cells from chronically hypoxic rats, like normoxic rats, possess O2-sensing mechanisms. However, they lack charybdotoxin-sensitive K+ channels that contribute to resting membrane potential in normoxically reared rats, and this appears to prevent them from depolarizing (and hence triggering Ca2+ influx and neurosecretion) during acute hypoxia.

Animals↗
PubMed1995

Calcium-dependent glutamate release during neuronal development and synaptogenesis: different involvement of omega-agatoxin IVA- and omega-conotoxin GVIA-sensitive channels.

Hippocampal neurons maintained in primary culture recycle synaptic vesicles and express functional glutamate receptors since early stages of neuronal development. By analyzing glutamate-induced cytosolic calcium changes to sense presynaptically released neurotransmitter, we demonstrate that the ability of neurons to release glutamate in the extracellular space is temporally coincident with the property of synaptic vesicles to undergo exocytotic-endocytotic recycling. Neuronal differentiation and maturation of synaptic contacts coincide with a change in the subtype of calcium channels primarily involved in controlling neurosecretion. Whereas omega-agatoxin IVA-sensitive channels play a role in controlling neurotransmitter secretion at all stages of neuronal differentiation, omega-conotoxin GVIA-sensitive channels are primarily involved in mediating glutamate release at early developmental stages only.

2-Amino-5-phosphonovalerate↗