Extracellular calcium acts as a “third messenger” to regulate enzyme and alkaline secretion

Abstract

It is generally assumed that the functional consequences of stimulation with Ca2+-mobilizing agonists are derived exclusively from the second messenger action of intracellular Ca2+, acting on targets inside the cells. However, during Ca2+ signaling events, Ca2+ moves in and out of the cell, causing changes not only in intracellular Ca2+, but also in local extracellular Ca2+. The fact that numerous cell types possess an extracellular Ca2+ “sensor” raises the question of whether these dynamic changes in external [Ca2+] may serve some sort of messenger function. We found that in intact gastric mucosa, the changes in extracellular [Ca2+] secondary to carbachol-induced increases in intracellular [Ca2+] were sufficient and necessary to elicit alkaline secretion and pepsinogen secretion, independent of intracellular [Ca2+] changes. These findings suggest that extracellular Ca2+ can act as a “third messenger” via Ca2+ sensor(s) to regulate specific subsets of tissue function previously assumed to be under the direct control of intracellular Ca2+.

The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure

“…and elicit intracellular responses in a paracrine fashion, acting in a way as a "third messenger" (10,23,24,29). On the basis of our observations in this study and the aforementioned considerations, we therefore propose a hypothesis of how the VSMC-CaSR and endothelial-CaSR could directly contribute to the maintenance of blood vessel tone (Fig.…”

In Vivo Epithelial Wound Repair Requires Mobilization of Endogenous Intracellular and Extracellular Calcium

“…In healthy tissue, carbachol increases both intracellular and luminal Ca 2ϩ in amphibian gastric glands, and this Ca 2ϩ extrusion into the gastric gland lumen is mediated by the plasma membrane Ca-ATPase (PMCA) 2 (7). Furthermore, luminal Ca 2ϩ is sufficient to elicit gastric secretions independently of intracellular Ca 2ϩ changes (7,8). Thus, luminal Ca 2ϩ contributes to the regulatory control of normal physiologic functions in the amphibian stomach.…”

NAADP, cADPR and IP3 all release Ca2+ from the endoplasmic reticulum and an acidic store in the secretory granule area

“…The crucial role of the IP 3 receptor (IP 3 R) was established by the discovery of high-affinity IP 3 Rbinding sites in the endoplasmic reticulum (ER) (Spät et al, 1986) and finally by the elucidation of the primary structure of this protein, which is both a Ca 2+ channel and an IP 3 -binding protein (Furuichi et al, 1989). IP 3 -elicited Ca 2+ release is now recognized as the principal mechanism for generation of Ca 2+ signals in electrically non-excitable cells, but it also plays an important role in many different types of cells that possess voltage-gated Ca 2+ channels (Berridge, 1993;Alvarez et al, 1999;Caroppo et al, 2004;Berridge et al, 2003). It is generally accepted that the ER is the most important organelle from which Ca 2+ can be released (Meldolesi and Pozzan, 1998), through either IP 3 Rs or ryanodine receptors (RyR) (Berridge, 1993;Petersen et al, 1994;Pozzan et al, 1994;Ashby et al, 2003b;Bootman et al, 2002), but other organelles can also store and release Ca 2+ .…”