Sigma-1 receptor regulation of voltage-gated calcium channels involves a direct interaction.
OBJECTIVE
The sigma-1 receptor belongs to a recently discovered family of transmembrane proteins expressed in the central nervous system, including the eye, and mediates the regulation of ion channels. The exact function of sigma receptors remains to be elucidated. The purpose of this study was to investigate the effect of sigma-1 receptor ligands on calcium homeostasis in a retinal ganglion cell line (RGC)-5 and rat primary RGCs.


METHODS
Calcium imaging was used to assess the effect of sigma-1 receptor agonist (+)-N-allylnormetazocine ((+)-SKF10047) on potassium chloride (KCl)-induced calcium influx in RGC-5. The whole-cell patch clamp technique was used to analyze the effect of (+)-SKF10047 on calcium currents in primary RGCs. Coimmunoprecipitation assessed the interaction between the sigma-1 receptor and the L-type voltage-gated calcium channel.


RESULTS
The sigma-1 receptor agonist (+)-SKF10047 inhibited potassium chloride (KCl)-induced calcium influx. The sigma-1 receptor antagonist, BD1047, reversed the inhibitory effect of (+)-SKF10047. Whole-cell patch clamp recordings of rat cultured primary RGCs demonstrated that (+)-SKF10047 inhibited calcium currents. Coimmunoprecipitation studies demonstrated an association between L-type calcium channels and the sigma-1 receptors.


CONCLUSIONS
These results suggest that sigma-1 receptor activation can regulate calcium homeostasis and signaling in RGCs, likely by directly influencing the activity of L-type voltage-gated calcium channels. Regulation of calcium influx in RGCs by sigma-1 receptor ligands may represent in part the neuroprotective effect of sigma-1 receptors.
Tchedre
Kissaou T
KT
Departments of Biomedical Science, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
Huang
Ren-Qi
RQ
Dibas
Adnan
A
Krishnamoorthy
Raghu R
RR
Dillon
Glenn H
GH
Yorio
Thomas
T
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D005029:Ethylenediamines / Q000494:pharmacology; D015870:Gene Expression; D007424:Intracellular Fluid / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000097605:Sigma-1 Receptor
D002118:Calcium; D020746:Calcium Channels, L-Type; D004247:DNA; D005029:Ethylenediamines; D010620:Phenazocine; D011189:Potassium Chloride; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C012134:SK&F 10047