Roles for Ca2+ Mobilization and Its Regulation in Mast Cell Functions

David Holowka,Deepti Gadi,Roy Cohen,Jinmin Lee,Norah L Smith,Barbara Baird,Nathaniel Calloway

doi:10.3389/fimmu.2012.00104

Abstract

Mobilization of Ca2+ in response to IgE receptor-mediated signaling is a key process in many aspects of mast cell function. Here we summarize our current understanding of the molecular bases for this process and the roles that it plays in physiologically relevant mast cell biology. Activation of IgE receptor signaling by antigen that crosslinks these complexes initiates Ca2+ mobilization as a fast wave that is frequently followed by a series of Ca2+ oscillations which are dependent on Ca2+ influx-mediated by coupling of the endoplasmic reticulum luminal Ca2+ sensor STIM1 to the calcium release activated calcium channel protein Orai1. Granule exocytosis depends on this process, together with the activation of protein kinase C isoforms, and specific roles for these signaling steps are beginning to be understood. Ca2+ mobilization also plays important roles in stimulated exocytosis of recycling endosomes and newly synthesized cytokines, as well as in antigen-mediated chemotaxis of rat mucosal mast cells. Phosphoinositide metabolism plays key roles in all of these processes, and we highlight these roles in several cases.

Highlights

Mast cell degranulation represents one of the earliest described examples of a Ca2+-dependent biological process in non-excitable cells (Foreman et al, 1973; Kanno et al, 1973)
In the present review we focus on the mechanisms by which FcεRI signaling mediates elevation of cytoplasmic Ca2+ and the consequences of this process in mast cell functional responses, including granule exocytosis, chemotaxis to antigen, and stimulated endosomal trafficking, including cytokine secretion and recycling endosomal exocytosis
A previous study in our laboratory provided evidence that different PI5-kinase family members synthesize functionally different pools of PIP2 (Vasudevan et al, 2009). To explore whether these functionally different pools of PIP2 might be synthesized in detergent-resistant ordered lipid domains and detergent-sensitive disordered lipid domains (Lingwood and Simons, 2010), we used transient expression of an inositol 5 -phosphatase that is targeted to either ordered or disordered lipids in RBL mast cells, and we found that the thapsigargin-stimulated association of STIM1 with

Summary

INTRODUCTION

Mast cell degranulation represents one of the earliest described examples of a Ca2+-dependent biological process in non-excitable cells (Foreman et al, 1973; Kanno et al, 1973). Release of Ca2+ from endoplasmic reticulum (ER) stores by antigen or thapsigargin (an irreversible inhibitor of the SERCA ATPase, which normally maintains high Ca2+ levels in the ER) is sufficient to activate Ca2+ influx necessary for degranulation from these cells (Wolfe et al, 1996). This Ca2+ influx mechanism is commonly referred to as store-operated Ca2+ entry (SOCE), and it was originally shown by Putney and colleagues to depend critically on depletion of luminal Ca2+ from the ER (Takemura et al, 1989). Our laboratory developed an imaging-based method to monitor the time-dependence of stimulated association of Orai with www.frontiersin.org

Calcium in mast cell functions

How might MARCKS contribute to enhancement of stimulated