An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells

• Published in: Neuropharmacology 2016-11, Vol.110 (Pt A), p.438-448
• Main Authors: Brindley, Rebecca L., Bauer, Mary Beth, Blakely, Randy D., Currie, Kevin P.M.
• Format: Article
• Language: English
• Subjects: 5-HT receptor; Adrenal chromaffin cell; Adrenal Glands - drug effects; Adrenal Glands - metabolism; Amperometry; Animals; Calcium - metabolism; Calcium channel; Calcium Channels, N-Type - metabolism; Calcium imaging; Catecholamine; Cations, Divalent - metabolism; Cells, Cultured; Chromaffin Cells - drug effects; Chromaffin Cells - metabolism; Exocytosis; Exocytosis - drug effects; Exocytosis - physiology; GPCR; Male; Membrane Potentials - drug effects; Membrane Potentials - physiology; Mice, Inbred C57BL; Mice, Knockout; Potassium Channels, Voltage-Gated - metabolism; Receptors, Serotonin - metabolism; Serotonin - metabolism; Serotonin Agents - pharmacology; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin transporter
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.08.015

Adrenal chromaffin cells (ACCs), the neuroendocrine arm of the sympathetic nervous system, secrete catecholamines to mediate the physiological response to stress. Although ACCs do not synthesize 5-HT, they express the serotonin transporter (SERT). Genetic variations in SERT are linked to several CNS disorders but the role(s) of SERT/5-HT in ACCs has remained unclear. Adrenal glands from wild-type mice contained 5-HT at ≈ 750 fold lower abundance than adrenaline, and in SERT−/− mice this was reduced by ≈80% with no change in catecholamines. Carbon fibre amperometry showed that SERT modulated the ability of 5-HT1A receptors to inhibit exocytosis. 5-HT reduced the number of amperometric spikes (vesicular fusion events) evoked by KCl in SERT−/− cells and wild-type cells treated with escitalopram, a SERT antagonist. The 5-HT1A receptor antagonist WAY100635 blocked the inhibition by 5-HT which was mimicked by the 5-HT1A agonist 8-OH-DPAT but not the 5-HT1B agonist CP93129. There was no effect on voltage-gated Ca2+ channels, K+ channels, or intracellular [Ca2+] handling, showing the 5-HT receptors recruit an atypical inhibitory mechanism. Spike charge and kinetics were not altered by 5-HT receptors but were reduced in SERT−/− cells compared to wild-type cells. Our data reveal a novel role for SERT and suggest that adrenal chromaffin cells might be a previously unrecognized hub for serotonergic control of the sympathetic stress response. [Display omitted] •Adrenal chromaffin cells (ACCs) in the sympathetic nervous system express SERT.•ACCs contain small amounts of 5-HT due to uptake by SERT.•SERT modulates the ability of 5-HT1A receptors to inhibit catecholamine release.•5-HT1A receptors recruit an atypical mechanism independent from Ca2+ or K+ channels.•ACCs might be an unrecognized hub for control of sympathoadrenal stress by SSRIs.