The Ryanodine Receptor Calcium Channel of β-Cells
Molecular Regulation and Physiological Significance
Molecular Regulation and Physiological Significance
Abstract
The list of Ca2+ channels involved in stimulus-secretion coupling in β-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 (RY) 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 β-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 β-cells some RY receptors are located on the secretory vesicles. Thus, despite their low abundance, RY receptors are emerging as distinct players in β-cell function by virtue of their large conductance, strategic locations, and their ability to amplify Ca2+ signals in a context-dependent manner.
Footnotes
-
Address correspondence and reprint requests to Md. Shahidul Islam, Associate Professor, Department of Molecular Medicine, Karolinska Institutet, Department of Endocrinology, Karolinska Hospital L1:02, S-171 76 Stockholm, Sweden. E-mail: shahidul.islam{at}molmed.ki.se.
Received for publication 6 November 2001 and accepted in revised form 14 January 2002.
[Ca2+]c, cytosolic free Ca2+ concentration; [Ca2+]m, mitochondrial Ca2+ concentration; CICR, Ca2+-induced Ca2+ release; ER, endoplasmic reticulum; FDP, fructose 1,6-diphosphate; KATP, ATP-sensitive potassium channel; IBMX, 3-isobutyl-1-methylxanthine; IP3R, IP3 receptor; NO, nitric oxide; PDE, phosphodiesterase; PKA, protein kinase A; RY, ryanodine.
- DIABETES