Sigma‐1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors

• Published in: Journal of neurochemistry Vol. 143; no. 2; pp. 171 - 182
• Main Authors: Brindley, Rebecca L., Bauer, Mary Beth, Hartley, Nolan D., Horning, Kyle J., Currie, Kevin P.M.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2017
• Subjects: Acetylcholine receptors (nicotinic); adrenal chromaffin cell; Adrenal glands; Adrenal Medulla - cytology; Adrenal Medulla - drug effects; Adrenal Medulla - metabolism; Animals; Anisoles - pharmacology; Antidepressants; Blocking; Calcium (intracellular); Calcium channels; Calcium channels (voltage-gated); Calcium influx; Carbachol; Catecholamine; Catecholamines; Catecholamines - antagonists & inhibitors; Catecholamines - metabolism; Cattle; Cells, Cultured; Chromaffin cells; Chromaffin Cells - drug effects; Chromaffin Cells - metabolism; Citalopram; Depolarization; Dose-Response Relationship, Drug; Drugs; Exocytosis; Fluvoxamine; Ion channels; Ligands; Male; Membrane potential; Mice; Mice, Inbred C57BL; Nerves; Neuropeptides; Nicotinic Antagonists - pharmacology; Propylamines - pharmacology; Proteins; Receptor mechanisms; Receptors; Receptors, Nicotinic - physiology; Receptors, sigma - agonists; Receptors, sigma - physiology; Secretion; Serotonin; Serotonin S1 receptors; Serotonin transporter; Serotonin uptake inhibitors; Sigma-1 Receptor; Stimulus-secretion coupling; Stress (physiology); Stress response; Sympathetic nervous system; sigma-1 receptor; adrenal chromaffin cell; catecholamine; serotonin transporter; calcium channels
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14149

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. Sigma‐1 receptors are intracellular chaperone proteins that can translocate to the plasma membrane to modulate various ion channels and cellular functions. We investigated the impact of several sigma‐1 receptor ligands including fluvoxamine (a selective serotonin reuptake inhibitor) on catecholamine secretion from adrenal chromaffin cells. Our data suggest that sigma‐1 receptors do not acutely regulate catecholamine secretion. Rather, sigma‐1 receptor ligands inhibited secretion evoked by cholinergic stimulation because of direct block of Ca2+entry via nicotinic acetylcholine receptors.