Electrical coupling between the human serotonin transporter and voltage-gated Ca(2+) channels.
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.
Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States.
Iwona
I
Ruchala
Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States.
Vanessa
V
Cabra
Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States.
Ernesto
E
Solis
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
Richard A
RA
Glennon
Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States.
Louis J
LJ
De Felice
Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: jmeltit@vcu.edu.
Jose M
JM
Eltit
D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D056966:Excitation Contraction Coupling / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D032446:Myoblasts / Q000187:drug effects / Q000502:physiology*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
D015220:Calcium Channels; D009467:Neuromuscular Depolarizing Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine
Calcium channels; Calcium imaging; Excitability; L-type calcium channel; Monoamine transporters; N-type calcium channel; Neurotransmitter transport; Skeletal muscle