Calcium Signaling in the Islets

Abstract

Easy access to rodent islets and insulinoma cells and the ease of measuring Ca(2+) by fluorescent indicators have resulted in an overflow of data that have clarified minute details of Ca(2+) signaling in the rodent islets. Our understanding of the mechanisms and the roles of Ca(2+) signaling in the human islets, under physiological conditions, has been hugely influenced by uncritical extrapolation of the rodent data obtained under suboptimal experimental conditions. More recently, electrophysiological and Ca(2+) studies have elucidated the ion channel repertoire relevant for Ca(2+) signaling in the human islets and have examined their relative importance. Many new channels belonging to the transient receptor potential (TRP) family are present in the beta-cells. Ryanodine receptors, nicotinic acid adenine dinucleotide phosphate channel, and Ca(2+)-induced Ca(2+) release add new dimension to the complexity of Ca(2+) signaling in the human beta-cells. A lot more needs to be learnt about the roles of these new channels and CICR, not because that will be easy but because that will be difficult. Much de-learning will also be needed. Human beta-cells do not have a resting state in the normal human body even under physiological fasting conditions. Their membrane potential under physiologically relevant resting conditions is approximately -50 mV. Biphasic insulin secretion is an experimental epiphenomenon unrelated to the physiological pulsatile insulin secretion into the portal vein in the human body. Human islets show a wide variety of electrical activities and patterns of [Ca(2+)](i) changes, whose roles in mediating pulsatile secretion of insulin into the portal vein remain questionable. Future studies will hopefully be directed toward a better understanding of Ca(2+) signaling in the human islets in the context of the pathogenesis and treatment of human diabetes.

Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic β cells

“…The intracellular sources of Ca 2+ include the endoplasmic reticulum (ER), endosomes and lysosomes (“acidic Ca 2+ stores”), and possibly the secretory granules. Collectively, these multiple mechanisms of Ca 2+ mobilization are considered to be processes of Ca 2+ -induced Ca 2+ release (CICR) in which metabolites such as IP 3 , cyclic ADP-ribose, or NAADP enhance the ability of cytosolic Ca 2+ to activate various Ca 2+ release channels located on intracellular organelles (Islam, 2010). …”

L-histidine sensing by calcium sensing receptor inhibits voltage-dependent calcium channel activity and insulin secretion in β-cells

“…In β-cells, the membrane depolarization caused by glucose metabolism, induces rapid conformational changes in L-type voltage dependent calcium channels (VDCC) that switches VDCC from a Ca 2+ -impermeable to a highly permeable Ca 2+ -pore that in turn allows extracellular calcium to enter the cytoplasm (Catterall 2000; Islam 2010). The Ca 2+ entry through VDCC directly induces trafficking of secretory granules and triggers insulin secretion (Islam 2010; Yang and Berggren 2005).…”

Junctophilin 3 expresses in pancreatic beta cells and is required for glucose-stimulated insulin secretion

“…23 Furthermore, sleep deprivation upregulates Jph3 transcription in mouse brain via stressful conditions through RyR-mediated intracellular calcium mobilization, 24 suggesting that Jph3 might also be a functional gene under stress in addition to its structural contribution. Given that Ca 2+ signaling in GSIS includes the amplifying features through K ATP -independent pathway, 6, 9, 25, 26 JPHs probably contribute to maintaining mitochondria function in beta cells. Importantly, the relationships between abnormal JPH isoforms and human diseases have also been confirmed.…”