Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors
| Autor: | Kyle J. Horning, Nolan D. Hartley, Kevin P. M. Currie, Rebecca L. Brindley, Mary Beth Bauer |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Agonist medicine.medical_specialty medicine.drug_class Chromaffin Cells Fluvoxamine Nicotinic Antagonists Anisoles Receptors Nicotinic Pharmacology Ligands Biochemistry Article Mice 03 medical and health sciences Cellular and Molecular Neuroscience Catecholamines 0302 clinical medicine Internal medicine medicine Animals Receptors sigma Nicotinic Antagonist Receptor Cells Cultured Acetylcholine receptor Dose-Response Relationship Drug Propylamines Chemistry Mice Inbred C57BL 030104 developmental biology Nicotinic agonist Endocrinology Adrenal Medulla Cholinergic Cattle 030217 neurology & neurosurgery Acetylcholine medicine.drug |
| Zdroj: | Journal of Neurochemistry. 143:171-182 |
| ISSN: | 0022-3042 |
| DOI: | 10.1111/jnc.14149 |
| Popis: | 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 Ca2+ channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT1A 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 [Ca2+ ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca2+ 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 Ca2+ entry via nAChRs. |
| Databáze: | OpenAIRE |
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