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Cell Calcium. 2014 Jul;56(1):25-33. doi: 10.1016/j.ceca.2014.04.003. Epub 2014 Apr 27.

Electrical coupling between the human serotonin transporter and voltage-gated Ca(2+) channels.

Author information

1
Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States.
2
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
3
Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: jmeltit@vcu.edu.

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.

KEYWORDS:

Calcium channels; Calcium imaging; Excitability; L-type calcium channel; Monoamine transporters; N-type calcium channel; Neurotransmitter transport; Skeletal muscle

PMID:
24854234
PMCID:
PMC4052380
DOI:
10.1016/j.ceca.2014.04.003
[Indexed for MEDLINE]
Free PMC Article
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