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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

[Ca²⁺]_i regulates trafficking of Ca_v1.3 (_1D Ca²⁺ channel) in insulin-secreting cells

¹Departments of Pharmacology, Tulane University Health Sciences Center and ⁴Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112; ²Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520; and ³Department of Pharmacology, Medical College of Virginia, Richmond, Virginia 23298

Submitted 12 August 2003 ; accepted in final form 25 September 2003

Chronic exposure of pancreatic -cells to high concentrations of glucose impairs the insulin secretory response to further glucose stimulation. This phenomenon is referred to as glucose desensitization. It has been shown that glucose desensitization is associated with abnormal elevation of -cell basal intracellular free Ca²⁺ concentration ([Ca²⁺]_i). We have investigated the relationship between the basal intracellular free Ca²⁺ and the L-type (Ca_v1.3) Ca²⁺ channel translocation in insulin-secreting cells. Glucose stimulation or membrane depolarization induced a nifedipine-sensitive Ca²⁺ influx, which was attenuated when the basal [Ca²⁺]_i was elevated. Using voltage-clamp techniques, we found that changing [Ca²⁺]_i could regulate the amplitude of the Ca²⁺ current. This effect was attenuated by drugs that interfere with the cytoskeleton. Immunofluorescent labeling of Ca_v1.3 showed an increase in the cytoplasmic distribution of the channels under high [Ca²⁺]_i conditions by deconvolution microscopy. The [Ca²⁺]_i-dependent translocation of Ca_v1.3 channel was also demonstrated by Western blot analysis of biotinylation/NeutrAvidin-bead-eluted surface proteins in cells preincubated at various [Ca²⁺]_i. These results suggest that Ca_v1.3 channel trafficking is involved in glucose desensitization of pancreatic -cells.

internalization; intracellular free calcium; glucose desensitization

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