Electrical coupling between the human serotonin transporter and voltage-gated Ca(2+) channels.
Iwona Ruchala, Vanessa Cabra, Ernesto Solis, Richard A Glennon, Louis J De Felice, Jose M. Eltit
Cell calcium July 2014 DOI: 10.1016/j.ceca.2014.04.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Cultured muscle cells genetically engineered to express hSERT, CaV1.1-null muscle cells, and HEK293T cells co-expressing hSERT with CaV1.3 or CaV2.2 |
| Interventions | 5HT S(+)MDMA |
| Topics | Serotonin |
| Keywords | Calcium channels Calcium imaging Excitability L-type calcium channel Monoamine transporters N-type calcium channel Neurotransmitter transport Skeletal muscle |
| Key findings | Serotonin and S(+)MDMA depolarized hSERT-expressing muscle cells and activated excitation-contraction coupling, but failed to do so in CaV1.1-null cells. In HEK293T cells, only co-expression with the lower-threshold L-type channel CaV1.3, not CaV2.2, produced calcium transients in response to 5HT or S(+)MDMA, and this coupling occurred at physiological serotonin concentrations. The authors propose this as a mechanism by which neurotransmitters or drugs like ecstasy could modulate calcium-driven signals. |
Abstract
Monoamine transporters have been implicated in dopamine or serotonin release in response to abused drugs such as methamphetamine or ecstasy (MDMA). In addition, monoamine transporters show substrate-induced inward currents that may modulate excitability and Ca(2+) mobilization, which could also contribute to neurotransmitter release. How monoamine transporters modulate Ca(2+) permeability is currently unknown. We investigate the functional interaction between the human serotonin transporter (hSERT) and voltage-gated Ca(2+) channels (CaV). We introduce an excitable expression system consisting of cultured muscle cells genetically engineered to express hSERT. Both 5HT and S(+)MDMA depolarize these cells and activate the excitation-contraction (EC)-coupling mechanism. However, hSERT substrates fail to activate EC-coupling in CaV1.1-null muscle cells, thus implicating Ca(2+) channels. CaV1.3 and CaV2.2 channels are natively expressed in neurons. When these channels are co-expressed with hSERT in HEK293T cells, only cells expressing the lower-threshold L-type CaV1.3 channel show Ca(2+) transients evoked by 5HT or S(+)MDMA. In addition, the electrical coupling between hSERT and CaV1.3 takes place at physiological 5HT concentrations. The electrical coupling between monoamine neurotransmitter transporters and Ca(2+) channels such as CaV1.3 is a novel mechanism by which endogenous substrates (neurotransmitters) or exogenous substrates (like ecstasy) could modulate Ca(2+)-driven signals in excitable cells.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 3
- The psychoactive drug 25B-NBOMe recapitulates rhabdomyolysis in zebrafish larvae Forensic Toxicology July 1, 2017
- The substrate import mechanism of the human serotonin transporter. Biophysical Journal March 1, 2022
- Cross-signaling in metabotropic glutamate 2 and serotonin 2A receptor heteromers in mammalian cells Pflügers Archiv: European Journal of Physiology January 16, 2016
Cites 3
- 3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans Addiction May 1, 1994
- Is ecstasy an empathogen? Biological Psychiatry December 1, 2010
- Is ecstasy an "empathogen"? Effects of ±3,4-methylenedioxymethamphetamine on prosocial feelings and identification of emotional states in others. Biological Psychiatry October 14, 2010