Nateglinide Stimulates Ca²⁺ Release from Endoplasmic Reticulum via Ryanodine Receptor Type 1

Abstract

Nateglinide, a D-phenylalanine derivative, is a non-sulfonylurea insulin secretagogue with a rapid onset and short duration of action. Nateglinideinduced insulin secretion is thought to be triggered by an increase in intracellular calcium (Ca²⁺) caused by binding with the Kir6.2/SUR1 complex and closure of the ATP-sensitive K⁺ (K_ATP) channel, similar to the sulfonylureas. However recently, another pathway for nateglinide-induced insulin secretion has been suggested, which is independent of the K_ATP channel and mediated by intracellular Ca²⁺ release from endoplasmic reticulum. To determine whether nateglinide can stimulate Ca²⁺ release from endoplasmic reticulum, we analyzed intracellular Ca²⁺ mobilization after the addition of nateglinide, using HEK293 cells with inducible expression of exogenous ryanodine receptor type 1 (RyR1) . Nateglinide increased intracellular Ca²⁺ concentration in a dose-dependent manner even in the absence of extracellular Ca²⁺ in cells expressing RyR1, but not in the non-induced cells. These results demonstrate that nateglinide activates RyR1 Ca²⁺ release channels, causing the increase in intracellular Ca²⁺ required to trigger insulin secretion.