Histamine Receptors Regulate the Activity, Surface Expression, and Phosphorylation of Serotonin Transporters.

Reuptake and clearance of released serotonin (5-HT) are critical in serotonergic neurotransmission. Serotonin transporter (SERT) is mainly responsible for clearing the extracellular 5-HT. Controlled trafficking, phosphorylation, and protein stability have been attributed to robust SERT activity. H histamine receptors (HRs) act in conjunction and regulate 5-HT release. HRs are expressed in the nervous system and located at the serotonergic terminals, where they act as heteroreceptors. Although histaminergic and serotonergic neurotransmissions are thought to be two separate events, whether HRs influence SERT in the CNS to control 5-HT reuptake has never been addressed. With knowledge gained from our studies, we explored the possibility of using rat hippocampal synaptosomal preparations. We found that treatment with HR/HR-agonists immepip and ()-(-)-α-methyl-histamine indeed resulted in a time- and concentration-dependent decrease in 5-HT transport. On the other hand, treatment with HR/HR-inverse agonist thioperamide caused a moderate increase in 5-HT uptake while blocking the inhibitory effect of HR/HR agonists. When investigated further, immepip treatment reduced the level of SERT on the plasma membrane and its phosphorylation. Likewise, CaMKII inhibitor KN93 or calcineurin inhibitor cyclosporine A also inhibited SERT function; however, an additive effect with immepip was not seen. High-speed chronoamperometry demonstrated that immepip delayed 5-HT clearance while thioperamide accelerated 5-HT clearance from the extracellular space. Immepip selectively inhibited SERT activity in the hippocampus and cortex but not in the striatum, midbrain, and brain stem. Thus, we report here a novel mechanism of regulating SERT activity by HR-mediated CaMKII/calcineurin pathway in a brain-region-specific manner and perhaps synaptic 5-HT in the CNS that controls 5-HT clearance.