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Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors.
Brindley RL, Bauer MB, Hartley ND, Horning KJ, Currie KPM
(2017) J Neurochem 143: 171-182
MeSH Terms: Adrenal Medulla, Animals, Anisoles, Catecholamines, Cattle, Cells, Cultured, Chromaffin Cells, Dose-Response Relationship, Drug, Ligands, Male, Mice, Mice, Inbred C57BL, Nicotinic Antagonists, Propylamines, Receptors, Nicotinic, Receptors, sigma
Show Abstract · Added September 28, 2017
Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 μM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca entry via nAChRs.
© 2017 International Society for Neurochemistry.
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16 MeSH Terms
Serotonin and Serotonin Transporters in the Adrenal Medulla: A Potential Hub for Modulation of the Sympathetic Stress Response.
Brindley RL, Bauer MB, Blakely RD, Currie KPM
(2017) ACS Chem Neurosci 8: 943-954
MeSH Terms: Adrenal Medulla, Animals, Arousal, Chromaffin Cells, Humans, Serotonin, Serotonin Plasma Membrane Transport Proteins, Stress, Physiological, Sympathetic Nervous System, Synaptic Transmission
Show Abstract · Added May 3, 2017
Serotonin (5-HT) is an important neurotransmitter in the central nervous system where it modulates circuits involved in mood, cognition, movement, arousal, and autonomic function. The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism. This review focuses on the role of SERT in the sympathetic nervous system. Autonomic/sympathetic dysfunction is evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. Experimentally, loss of SERT function (SERT knockout mice or chronic pharmacological block) has been reported to augment the sympathetic stress response. Alterations to serotonergic signaling in the CNS and thus central drive to the peripheral sympathetic nervous system are presumed to underlie this augmentation. Although less widely recognized, SERT is robustly expressed in chromaffin cells of the adrenal medulla, the neuroendocrine arm of the sympathetic nervous system. Adrenal chromaffin cells do not synthesize 5-HT but accumulate small amounts by SERT-mediated uptake. Recent evidence demonstrated that 5-HT receptors inhibit catecholamine secretion from adrenal chromaffin cells via an atypical mechanism that does not involve modulation of cellular excitability or voltage-gated Ca channels. This raises the possibility that the adrenal medulla is a previously unrecognized peripheral hub for serotonergic control of the sympathetic stress response. As a framework for future investigation, a model is proposed in which stress-evoked adrenal catecholamine secretion is fine-tuned by SERT-modulated autocrine 5-HT signaling.
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10 MeSH Terms
Glucocorticoid-deficient corticotropin-releasing hormone knockout mice maintain glucose requirements but not autonomic responses during repeated hypoglycemia.
Jacobson L, Ansari T, Potts J, McGuinness OP
(2006) Am J Physiol Endocrinol Metab 291: E15-22
MeSH Terms: Adrenal Medulla, Animals, Autonomic Nervous System, Blood Glucose, Corticosterone, Corticotropin-Releasing Hormone, Epinephrine, Glucagon, Glucocorticoids, Glucose, Glucose Clamp Technique, Hypoglycemia, Insulin, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Norepinephrine
Show Abstract · Added July 21, 2014
Glucocorticoids have been implicated in hypoglycemia-induced autonomic failure but also contribute to normal counterregulation. To determine the influence of normal and hypoglycemia-induced levels of glucocorticoids on counterregulatory responses to acute and repeated hypoglycemia, we compared plasma catecholamines, corticosterone, glucagon, and glucose requirements in male wild-type (WT) and glucocorticoid-deficient, corticotropin-releasing hormone knockout (CRH KO) mice. Conscious, chronically cannulated, unrestrained WT and CRH KO mice underwent a euglycemic (Prior Eu) or hypoglycemic clamp (Prior Hypo) on day 1 followed by a hypoglycemic clamp on day 2 (blood glucose both days, 65 +/- 1 mg/dl). Baseline epinephrine and glucagon were similar, and norepinephrine was elevated, in CRH KO vs. WT mice. CRH KO corticosterone was almost undetectable (<1.5 microg/dl) and unresponsive to hypoglycemia. CRH KO glucose requirements were significantly higher during day 1 hypoglycemia despite epinephrine and glucagon responses that were comparable to or greater than those in WT. Hyperinsulinemic euglycemia did not increase hormones or glucose requirements above baseline. On day 2, Prior Hypo WT had significantly higher glucose requirements and significantly lower corticosterone and glucagon responses. Prior Hypo and Prior Eu CRH KO mice had similar day 2 glucose requirements. However, Prior Hypo CRH KO mice had significantly lower day 2 epinephrine and norepinephrine vs. Prior Eu CRH KO and tended to have lower glucagon than on day 1. We conclude that glucocorticoid insufficiency in CRH KO mice correlates with 1) impaired counterregulation during acute hypoglycemia and 2) complex effects after repeated hypoglycemia, neither preventing decreased hormone responses nor worsening glucose requirements.
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18 MeSH Terms
Modafinil elicits sympathomedullary activation.
Taneja I, Diedrich A, Black BK, Byrne DW, Paranjape SY, Robertson D
(2005) Hypertension 45: 612-8
MeSH Terms: Adrenal Medulla, Adult, Benzhydryl Compounds, Cardiovascular System, Catecholamines, Central Nervous System Stimulants, Cross-Over Studies, Diuresis, Double-Blind Method, Electrolytes, Female, Humans, Male, Middle Aged, Modafinil, Muscle, Skeletal, Reference Values, Sympathetic Nervous System
Show Abstract · Added December 10, 2013
The autonomic effects of modafinil (Provigil), a psychostimulant widely used to attenuate fatigue and promote wakefulness, are currently unexplored. We assessed the effect of modafinil on autonomic nervous system. We compared oral modafinil (400 mgx1) versus placebo in 12 healthy hospitalized normal subjects in a randomized double-blind, placebo-controlled cross-over study for 3 days each with subjects in 150 mEq sodium, 70 mEq potassium balance at the Vanderbilt General Clinical Research Center. Modafinil increased resting heart rate (9.2+/-2.0 bpm; mean [+/-SE]; 95% confidence interval [CI], 4.7 to 13.6; P=0.001), resting systolic blood pressure (7.3+/-3.2 mm Hg; 95% CI, 0.2 to 14.4; P=0.044), and resting diastolic blood pressure (5.3+/-1.7 mm Hg; 95% CI, 1.4 to 9.1 mm Hg; P<0.012). Modafinil elicited a 42% higher orthostatic increase in plasma norepinephrine (0.8+/-0.3 nmol/L; 95% CI, 0.2 to 1.3; P=0.01), and caused a 33% increase in urine norepinephrine (5.1+/-1.1 nmol/L creatinine per day; 95% CI, 2.7 to 7.4, P=0.001), and an 81% increase in urine epinephrine (1.3+/-0.2 nmol/L creatinine per day; 95% CI, 1 to 2; P<0.001). The peroneal microneurographic sympathetic activity was attenuated by modafinil during orthostatic tilt (P<0.001). alpha1-Adrenoreceptor function was maintained. Modafinil substantially perturbs autonomic cardiovascular regulation by increase in heart rate and blood pressure. Autonomic changes of this magnitude encourage caution in use of modafinil in patients with cardiovascular disease.
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18 MeSH Terms
Cause for excite-M-ent in adrenal chromaffin cells.
Currie KP, Fox AP
(2002) J Physiol 540: 729
MeSH Terms: Adrenal Medulla, Animals, Cattle, Chromaffin Cells, Membrane Potentials, Potassium Channels
Added March 30, 2013
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6 MeSH Terms
Evidence for paracrine signaling between macrophages and bovine adrenal chromaffin cell Ca(2+) channels.
Currie KP, Zhou Z, Fox AP
(2000) J Neurophysiol 83: 280-7
MeSH Terms: Adrenal Medulla, Animals, Calcium Channels, Cattle, Cell Line, Cells, Cultured, Chromaffin Cells, Coculture Techniques, Dinoprostone, GTP-Binding Proteins, Ibuprofen, Interleukin-1, Interleukin-6, Lipopolysaccharides, Macrophages, Masoprocol, Mice, Patch-Clamp Techniques, Pertussis Toxin, Signal Transduction, Virulence Factors, Bordetella
Show Abstract · Added March 30, 2013
The adrenal gland contains resident macrophages, some of which lie adjacent to the catecholamine producing chromaffin cells. Because macrophages release a variety of secretory products, it is possible that paracrine signaling between these two cell types exists. Of particular interest is the potential paracrine modulation of voltage-gated calcium channels (I(Ca)), which are the main calcium influx pathway triggering catecholamine release from chromaffin cells. We report that prostaglandin E(2) (PGE(2)), one of the main signals produced by macrophages, inhibited I(Ca) in cultured bovine adrenal chromaffin cells. The inhibition is rapid, robust, and voltage dependent; the activation kinetics are slowed and inhibition is largely reversed by a large depolarizing prepulse, suggesting that the inhibition is mediated by a direct G-protein betagamma subunit interaction with the calcium channels. About half of the response to PGE(2) was sensitive to pertussis toxin (PTX) incubation, suggesting both PTX-sensitive and -insensitive G proteins were involved. We show that activation of macrophages by endotoxin rapidly (within minutes) releases a signal that inhibits I(Ca) in chromaffin cells. The inhibition is voltage dependent and partially PTX sensitive. PGE(2) is not responsible for this inhibition as blocking cyclooxygenase with ibuprofen did not prevent the production of the inhibitory signal by the macrophages. Nor did blocking the lipoxygenase pathway with nordihydroguaiaretic acid alter production of the inhibitory signal. Our results suggest that macrophages may modulate I(Ca) and catecholamine secretion by releasing PGE(2) and other chemical signal(s).
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21 MeSH Terms
Comparison of N- and P/Q-type voltage-gated calcium channel current inhibition.
Currie KP, Fox AP
(1997) J Neurosci 17: 4570-9
MeSH Terms: Adenosine Triphosphate, Adrenal Medulla, Animals, Calcium Channel Blockers, Calcium Channels, Cattle, Cells, Cultured, Chromaffin Cells, GTP-Binding Proteins, Guanosine 5'-O-(3-Thiotriphosphate), Kinetics, Membrane Potentials, Patch-Clamp Techniques, Peptides, Sodium Channels, Spider Venoms, Time Factors, omega-Agatoxin IVA, omega-Conotoxin GVIA
Show Abstract · Added March 30, 2013
Activation of N- and P/Q-type voltage-gated calcium channels triggers neurotransmitter release at central and peripheral synapses. These channels are targets for regulatory mechanisms, including inhibition by G-protein-linked receptors. Inhibition of P/Q-type channels has been less well studied than the extensively characterized inhibition of N-type channels, but it is thought that they are inhibited by similar mechanisms although possibly to a lesser extent than N-type channels. The aim of this study was to compare the inhibition of the two channel types. Calcium currents were recorded from adrenal chromaffin cells and isolated by the selective blockers omega-conotoxin GVIA (1 microM) and omega-agatoxin IVA (400 nM). The inhibition was elicited by ATP (100 microM) or intracellular application of GTP-gamma-S. It was classified as voltage-sensitive (relieved by a conditioning prepulse) or voltage-insensitive (present after a conditioning prepulse). The voltage-insensitive inhibition accounted for a 20% reduction of both currents, whereas the voltage-sensitive inhibition reduced the N-type current by 45% but the P/Q-type current by 18%. However, the voltage dependence of the inhibition, the time course of relief from inhibition during a conditioning prepulse, and the time course of reinhibition after such a prepulse showed few differences between the N- and P/Q-type channels. Assuming a simple bimolecular reaction, our data suggest that changes in the kinetics of the G-protein/channel interaction alone cannot explain the differences in the inhibition of the N- and P/Q-type calcium channels. The subtle differences in inhibition may facilitate the selective regulation of neurotransmitter release.
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19 MeSH Terms
ATP serves as a negative feedback inhibitor of voltage-gated Ca2+ channel currents in cultured bovine adrenal chromaffin cells.
Currie KP, Fox AP
(1996) Neuron 16: 1027-36
MeSH Terms: Adenosine Triphosphate, Adrenal Medulla, Animals, Calcium, Calcium Channel Blockers, Calcium Channels, Cattle, Cells, Cultured, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Enkephalins, Ion Channel Gating, Membrane Potentials, Naloxone, Triazines
Show Abstract · Added March 30, 2013
Modulation of voltage-gated Ca(2+) channel current (I(Ca)) regulates secretion of catecholamines from adrenal chromaffin cells. Previous work demonstrated that I(Ca) can be augmented by phosphorylation to increase secretion or that inhibition of I(Ca) results in diminished catecholamine secretion. In the current manuscript, we show that stimulation of chromaffin cells results in the release of an "endogenous inhibitor" that suppresses I(Ca). The inhibition is due to the secretion of ATP, which is stored at high concentrations in secretory granules and is coreleased with catecholamines upon stimulation. The ATP exerts its actions through P(2 gamma) purinoceptors and inhibits both N- and P/Q-type Ca (2+) channels in a voltage-dependent manner but with different efficacies. Overall, we have identified and characterized a negative feedback pathway that may serve as an important regulatory mechanism for catecholamine secretion in chromaffin cells.
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14 MeSH Terms
Sympathoadrenal regulation of adrenocortical steroidogenesis.
Ehrhart-Bornstein M, Bornstein SR, González-Hernández J, Holst JJ, Waterman MR, Scherbaum WA
(1995) Endocr Res 21: 13-24
MeSH Terms: Adrenal Cortex, Adrenal Cortex Hormones, Adrenal Glands, Adrenal Medulla, Adult, Animals, Cattle, Cells, Cultured, Humans, Middle Aged, Perfusion, Steroids, Swine, Sympathetic Nervous System
Show Abstract · Added February 12, 2015
Sympathoadrenal regulation of adrenocortical steroidogenesis was studied on a physiological, cellular, molecular and morphological level. The effects of nerve activation and of epinephrine (EPI) on adrenal corticosteroid release were compared in isolated perfused pig adrenals with preserved nerve supply. Splanchnic nerve activation as well as perfusion with EPI provoked a significant release of cortisol, aldosterone and androstenedione. In cultured bovine adrenocortical cells steroid secretion and accumulation of P450scc, P450(17) alpha, P450c21 and P450(11) beta mRNAs were studied after stimulation with EPI with or without propranolol or phentolamine. Incubation with EPI stimulated steroidogenesis and increased the levels of all four P450-mRNAs. The beta-adrenergic antagonist propranolol totally blocked the effects of EPI while the alpha-antagonist phentolamine had no effect. Using immunohistochemistry, adrenals were studied morphologically. The contact zones of the two cell types were investigated on an electron microscopical level. Cortical and medullary cells were closely interwoven with cortical and chromaffin cells in direct apposition, providing the possibility for paracrine interactions. It is concluded that the release of corticosteroids can be stimulated through the sympatho-adrenal system. The stimulatory action of EPI upon adrenal steroid formation and accumulation of all four P450-mRNAs requires beta-adrenergic receptors. Taking into consideration the close colocalization of cortical and medullary tissue, this stimulation may be mediated by chromaffin cells in a paracrine manner.
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14 MeSH Terms