An Interplay Between the Serotonin Transporter (SERT) and 5-HT Receptors Controls Stimulus-secretion Coupling in Sympathoadrenal Chromaffin Cells

Overview

Journal Neuropharmacology

Specialties Neurology
Pharmacology

Date 2016 Aug 22

PMID 27544824

Citations 10

Authors

Rebecca L Brindley

Mary Beth Bauer

Randy D Blakely

Kevin P M Currie

Affiliations

Soon will be listed here.

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.

Citing Articles

The Influence of Serotonergic Signaling on Quality of Life, Depression, Insomnia, and Hypoxia in Obstructive Sleep Apnea Patients: Cross-Sectional Study.

Ditmer M, Gabryelska A, Turkiewicz S, Gajewski A, Bialasiewicz P, Chalubinski M J Clin Med. 2025; 14(2).

PMID: 39860451 PMC: 11766041. DOI: 10.3390/jcm14020445.

Serotonin and the serotonin transporter in the adrenal gland.

Bauer M, Currie K Vitam Horm. 2024; 124:39-78.

PMID: 38408804 PMC: 11217909. DOI: 10.1016/bs.vh.2023.06.002.

Serotonergic Modulation of Neurovascular Transmission: A Focus on Prejunctional 5-HT Receptors/Mechanisms.

Gonzalez-Hernandez A, Marichal-Cancino B, MaassenVanDenBrink A, Villalon C Biomedicines. 2023; 11(7).

PMID: 37509503 PMC: 10377335. DOI: 10.3390/biomedicines11071864.

Phospholipase C-ε defines a PACAP-stimulated pathway for secretion in the chromaffin cell.

Chen X, Coffman B, Brindley R, Galpin J, Ahern C, Currie K J Neuroendocrinol. 2023; 35(11):e13255.

PMID: 36970756 PMC: 10790106. DOI: 10.1111/jne.13255.

PACAP and acetylcholine cause distinct Ca2+ signals and secretory responses in chromaffin cells.

Morales A, Mohan R, Chen X, Coffman B, Bendahmane M, Watch L J Gen Physiol. 2022; 155(2).

PMID: 36538657 PMC: 9770323. DOI: 10.1085/jgp.202213180.

References

Muma N, Mi Z . Serotonylation and Transamidation of Other Monoamines. ACS Chem Neurosci. 2015; 6(7):961-9. DOI: 10.1021/cn500329r. View

Luscher C, Jan L, Stoffel M, Malenka R, Nicoll R . G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron. 1997; 19(3):687-95. DOI: 10.1016/s0896-6273(00)80381-5. View

Currie K, Fox A . Differential facilitation of N- and P/Q-type calcium channels during trains of action potential-like waveforms. J Physiol. 2002; 539(Pt 2):419-31. PMC: 2290166. DOI: 10.1113/jphysiol.2001.013206. View

Linder A, Beggs K, Burnett R, Watts S . Body distribution of infused serotonin in rats. Clin Exp Pharmacol Physiol. 2009; 36(5-6):599-601. DOI: 10.1111/j.1440-1681.2009.05147.x. View

Courtney N, Ford C . Mechanisms of 5-HT1A receptor-mediated transmission in dorsal raphe serotonin neurons. J Physiol. 2015; 594(4):953-65. PMC: 4753271. DOI: 10.1113/JP271716. View

Murphy D, Fox M, Timpano K, Moya P, Ren-Patterson R, Andrews A . How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. Neuropharmacology. 2008; 55(6):932-60. PMC: 2730952. DOI: 10.1016/j.neuropharm.2008.08.034. View

Currie K . Inhibition of Ca2+ channels and adrenal catecholamine release by G protein coupled receptors. Cell Mol Neurobiol. 2010; 30(8):1201-8. PMC: 3028936. DOI: 10.1007/s10571-010-9596-7. View

Meyer J, Wilson A, Sagrati S, Hussey D, Carella A, Potter W . Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry. 2004; 161(5):826-35. DOI: 10.1176/appi.ajp.161.5.826. View

Garcia A, Garcia-de-Diego A, Gandia L, Borges R, Garcia-Sancho J . Calcium signaling and exocytosis in adrenal chromaffin cells. Physiol Rev. 2006; 86(4):1093-131. DOI: 10.1152/physrev.00039.2005. View

10.

Livett B, Dean D, Whelan L, UDENFRIEND S, Rossier J . Co-release of enkephalin and catecholamines from cultured adrenal chromaffin cells. Nature. 1981; 289(5795):317-9. DOI: 10.1038/289317a0. View

11.

Watts S, Morrison S, Davis R, Barman S . Serotonin and blood pressure regulation. Pharmacol Rev. 2012; 64(2):359-88. PMC: 3310484. DOI: 10.1124/pr.111.004697. View

12.

Briscoe V, Ertl A, Tate D, Dawling S, Davis S . Effects of a selective serotonin reuptake inhibitor, fluoxetine, on counterregulatory responses to hypoglycemia in healthy individuals. Diabetes. 2008; 57(9):2453-60. PMC: 2518497. DOI: 10.2337/db08-0236. View

13.

Ye R, Blakely R . Natural and engineered coding variation in antidepressant-sensitive serotonin transporters. Neuroscience. 2011; 197:28-36. PMC: 3850749. DOI: 10.1016/j.neuroscience.2011.08.056. View

14.

Betke K, Wells C, Hamm H . GPCR mediated regulation of synaptic transmission. Prog Neurobiol. 2012; 96(3):304-21. PMC: 3319362. DOI: 10.1016/j.pneurobio.2012.01.009. View

15.

Hagan C, McDevitt R, Liu Y, Furay A, Neumaier J . 5-HT(1B) autoreceptor regulation of serotonin transporter activity in synaptosomes. Synapse. 2012; 66(12):1024-34. PMC: 3472085. DOI: 10.1002/syn.21608. View

16.

Currie K, Fox A . ATP serves as a negative feedback inhibitor of voltage-gated Ca2+ channel currents in cultured bovine adrenal chromaffin cells. Neuron. 1996; 16(5):1027-36. DOI: 10.1016/s0896-6273(00)80126-9. View

17.

Fulop T, Smith C . Matching native electrical stimulation by graded chemical stimulation in isolated mouse adrenal chromaffin cells. J Neurosci Methods. 2007; 166(2):195-202. PMC: 2464294. DOI: 10.1016/j.jneumeth.2007.07.004. View

18.

Bayliss D, Li Y, Talley E . Effects of serotonin on caudal raphe neurons: activation of an inwardly rectifying potassium conductance. J Neurophysiol. 1997; 77(3):1349-61. DOI: 10.1152/jn.1997.77.3.1349. View

19.

Weiss A, Anantharam A, Bittner M, Axelrod D, Holz R . Lumenal protein within secretory granules affects fusion pore expansion. Biophys J. 2014; 107(1):26-33. PMC: 4119268. DOI: 10.1016/j.bpj.2014.04.064. View

20.

Winkler H, Westhead E . The molecular organization of adrenal chromaffin granules. Neuroscience. 1980; 5(11):1803-23. DOI: 10.1016/0306-4522(80)90031-7. View