The ryanodine receptor calcium channel of β-cells -: Molecular regulation and physiological significance

The list of Ca2+ channels involved in stimulus-secretion coupling in beta-cells is increasing. In this respect the roles of the voltage-gated Ca2+ channels and IP3 receptors are well accepted. There is a lack of consensus about the significance of a third group of Ca2+ channels called ryanodine (R receptors. These are large conduits located on Ca2+ storage organelle. Ca2+ gates these channels in a concentration- and time-dependent manner. Activation of these channels by Ca2+ leads to fast release of Ca2+ from the stores, a process called Ca2+- induced Ca2+ release (CICR). A substantial body of evidence confirms that beta-cells have RY receptors. CICR by RY receptors amplifies Ca2+ signals. Some properties of RY receptors ensure that this amplification process is engaged in a context-dependent manner. Several endogenous molecules and processes that modulate RY receptors determine the appropriate context. Among these are several glycolytic intermediates, long-chain acyl CoA, ATP, cAMP, cADPR, NO, and high luminal Ca2+ concentration, and all of these have been shown to sensitize RY receptors to the trigger action of Ca2+. RY receptors, thus, detect co-incident signals and integrate them. These Ca2+ channels are targets for the action of cAMP-linked incretin hormones that stimulate glucose-dependent insulin secretion. In beta-cells some RY receptors are located on the secretory vesicles. Thus, despite their low abundance, RY receptors are emerging as distinct players in beta-cell function by virtue of their large conductance, strategic locations, and their ability to amplify Ca2+ signals in a context-dependent manner.