title: An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells.
abstract: 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 Ca(2+) channels, K(+) channels, or intracellular [Ca(2+)] 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.
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Brindley
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Bauer
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: kevin.currie@vanderbilt.edu.
authors.forename: Kevin P M
authors.initials: KPM
authors.lastname: Currie
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020864:Calcium Channels, N-Type; D002413:Cations, Divalent; D024642:Potassium Channels, Voltage-Gated; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D002118:Calcium
keywords: 5-HT receptor; 8-OH-DPAT (PubChem CID: 6917794); Adrenal chromaffin cell; Amperometry; CP93129 (PubChem CID: 124007); Calcium channel; Calcium imaging; Catecholamine; Escitalopram (PubChem CID: 146571); Exocytosis; GPCR; Gallein (PubChem CID: 73685); Serotonin hydrochloride (PubChem CID: 160436); Serotonin transporter; WAY100635 (PubChem CID: 11957721)