The Serotonin Transporter Modulates the Quantal Size of Vesicular Release Events in Adrenal Chromaffin Cells

Abstract

The serotonin (5-HT) transporter (SERT) is an important regulator of 5-HT signaling in the CNS. SERT is also expressed in adrenal chromaffin cells (ACCs), part of the sympathetic nervous system that coordinates the physiological response to stress through exocytosis of catecholamines and other transmitters. Here, we used carbon fiber amperometry to show that SERT modulates catecholamine secretion from ACCs by at least two distinct mechanisms. First, SERT accumulates small amounts of 5-HT into ACCs and modulates the ability of 5-HT1A receptors to inhibit the number of vesicular fusion events in isolated ACCs. Additionally, SERT acts via a mechanism independent of 5-HT1A receptor activation to modulate the amount and kinetics of transmitter release from individual vesicular fusion events. The half-width (duration) and charge (amount of oxidizable transmitter released) of individual amperometric spikes (vesicular fusion events) was significantly smaller (∼35%) in SERT−/− cells compared to wild-type. The same effect was recapitulated in wild-type cells by in vitro pharmacological block of SERT (∼48hrs culture with escitalopram) or by restricting the amount of extracellular 5-HT available for uptake (∼48hrs culture dialyzed serum media). Adrenal 5-HT content is determined by SERT-mediated uptake but only accounts for a small fraction (∼0.13%) of the total adrenal gland monoamine content. Although 5-HT content was reduced in SERT−/− adrenal glands, the catecholamine content was unaltered making it unlikely that the reduced spike charge (35% decrease) is simply due to reduced vesicular monoamine content. Ongoing work will dissect the underlying mechanisms by which adrenal SERT / 5-HT regulate catecholamine secretion and hence the sympathoadrenal stress response.