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.