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Ca_v1.3 Is Preferentially Coupled to Glucose-Induced [Ca²⁺]_i Oscillations in the Pancreatic Cell Line INS-1

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences (G.L., N.H., G.H.), and the Graduate Program in Neuroscience (G.L.), Purdue University, West Lafayette, Indiana

The link between Ca²⁺ influx through the L-type calcium channels Ca_v1.2 or Ca_v1.3 and glucose- or KCl-induced [Ca²⁺]_i mobilization in INS-1 cells was assessed using the calcium indicator indo-1. Cells responded to 18 mM glucose or 50 mM KCl stimulation with different patterns in [Ca²⁺]_i increases, although both were inhibited by 10 µM nifedipine. Although KCl elicited a prolonged elevation in [Ca²⁺]_i, glucose triggered oscillations in [Ca²⁺]_i. Ca_v1.2/dihydropyridine-insensitive (DHPi) cells and Ca_v1.3/DHPi cells, and stable INS-1 cell lines expressing either DHP-insensitive Ca_v1.2 or Ca_v1.3 channels showed normal responses to glucose. However, in 10 µM nifedipine, only Ca_v1.3/DHPi cells maintained glucose-induced [Ca²⁺]_i oscillation. In contrast, both cell lines exhibited DHP-resistant [Ca²⁺]_i increases in response to KCl. The percentage of cells responding to glucose was not significantly decreased by nifedipine in Ca_v1.3/DHPi cells but was greatly reduced in Ca_v1.2/DHPi cells. In 10 µM nifedipine, KCl-elicited [Ca²⁺]_i elevation was retained in both Ca_v1.2/DHPi and Ca_v1.3/DHPi cells. In INS-1 cells expressing the intracellular II-III loop of Ca_v1.3, glucose failed to elicit [Ca²⁺]_i changes, whereas INS-1 cells expressing the Ca_v1.2 II-III loop responded to glucose with normal [Ca²⁺]_i oscillation. INS-1 cells expressing Ca_v1.2/DHPi containing the II-III loop of Ca_v1.3 demonstrated a nifedipine-resistant slow increase in [Ca²⁺]_i and nifedipine-resistant insulin secretion in response to glucose that was partially inhibited by diltiazem. Thus, whereas the II-III loop of Ca_v1.3 may be involved in coupling Ca²⁺ influx to insulin secretion, distinct structural domains are required to mediate the preferential coupling of Ca_v1.3 to glucose-induced [Ca²⁺]_i oscillation.

Address correspondence to: Dr. Gregory Hockerman, 575 Stadium Mall Drive, West Lafayette, IN 47907-2091. E-mail: gregh{at}pharmacy.purdue.edu

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