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Originally published In Press as doi:10.1167/iovs.08-1867 on July 18, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4993-5002.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-1867
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Sigma-1 Receptor Regulation of Voltage-Gated Calcium Channels Involves a Direct Interaction

Kissaou T. Tchedre,1 Ren-Qi Huang,2 Adnan Dibas,2 Raghu R. Krishnamoorthy,2 Glenn H. Dillon,2 and Thomas Yorio2

1From the Departments of Biomedical Sciences and 2Pharmacology and Neurosciences, University of North Texas Health Science Center, Fort Worth, Texas.

PURPOSE. The {varsigma}-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 {varsigma}-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 {varsigma}-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 {varsigma}-1 receptor and the L-type voltage-gated calcium channel.

RESULTS. The {varsigma}-1 receptor agonist (+)-SKF10047 inhibited potassium chloride (KCl)-induced calcium influx. The {varsigma}-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 {varsigma}-1 receptors.

CONCLUSIONS. These results suggest that {varsigma}-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 {varsigma}-1 receptor ligands may represent in part the neuroprotective effect of {varsigma}-1 receptors.




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Voltage-gated sodium channel modulation by {sigma}-receptors in cardiac myocytes and heterologous systems
Am J Physiol Cell Physiol, May 1, 2009; 296(5): C1049 - C1057.
[Abstract] [Full Text] [PDF]


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