House dust mite allergens, store-operated Ca channels and asthma.

The house dust mite is the principal source of aero-allergen worldwide. Exposure to mite-derived allergens is associated with the development of asthma in susceptible individuals, and the majority of asthmatics are allergic to the mite. Mite-derived allergens are functionally diverse and activate multiple cell types within the lung that result in chronic inflammation.

A Reappraisal of the Effects of L-type Ca Channel Blockers on Store-Operated Ca Entry and Heart Failure.

Dihydropyridines such as amlodipine are widely used as antihypertensive agents, being prescribed to ∼70 million Americans and >0.4 billion adults worldwide. Dihydropyridines block voltage-gated Ca channels in resistance vessels, leading to vasodilation and a reduction in blood pressure.

Plasma Membrane Ca ATPase Activity Enables Sustained Store-operated Ca Entry in the Absence of a Bulk Cytosolic Ca Rise.

In many cell types, the rise in cytosolic Ca due to opening of Ca release-activated Ca (CRAC) channels drives a plethora of responses, including secretion, motility, energy production, and gene expression. The amplitude and time course of the cytosolic Ca rise is shaped by the rates of Ca entry into and removal from the cytosol. However, an extended bulk Ca rise is toxic to cells.

Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation.

Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1.

AKAP79 Orchestrates a Cyclic AMP Signalosome Adjacent to Orai1 Ca Channels.

To ensure specificity of response, eukaryotic cells often restrict signalling molecules to sub-cellular regions. The Ca nanodomain is a spatially confined signal that arises near open Ca channels. Ca nanodomains near store-operated Orai1 channels stimulate the protein phosphatase calcineurin, which activates the transcription factor NFAT1, and both enzyme and target are initially attached to the plasma membrane through the scaffolding protein AKAP79.

Store-Operated Ca Channels: Mechanism, Function, Pharmacology, and Therapeutic Targets.

Calcium (Ca) release-activated Ca (CRAC) channels are a major route for Ca entry in eukaryotic cells. These channels are store operated, opening when the endoplasmic reticulum (ER) is depleted of Ca, and are composed of the ER Ca sensor protein STIM and the pore-forming plasma membrane subunit Orai. Recent years have heralded major strides in our understanding of the structure, gating, and function of the channels.

Signaling through Ca Microdomains from Store-Operated CRAC Channels.

Calcium (Ca) ion microdomains are subcellular regions of high Ca concentration that develop rapidly near open Ca channels in the plasma membrane or internal stores and generate local regions of high Ca concentration. These microdomains are remarkably versatile in that they activate a range of responses that differ enormously in both their temporal and spatial profile. In this review, we describe how Ca microdomains generated by store-operated calcium channels, a widespread and conserved Ca entry pathway, stimulate different signaling pathways, and how the spatial extent of a Ca microdomain can be influenced by Ca ATPase pumps.

Selective recruitment of different Ca-dependent transcription factors by STIM1-Orai1 channel clusters.

Store-operated Ca entry, involving endoplasmic reticulum Ca sensing STIM proteins and plasma membrane Orai1 channels, is a widespread and evolutionary conserved Ca influx pathway. This form of Ca influx occurs at discrete loci where peripheral endoplasmic reticulum juxtaposes the plasma membrane. Stimulation evokes numerous STIM1-Orai1 clusters but whether distinct signal transduction pathways require different cluster numbers is unknown.

The whole-cell Ca release-activated Ca current, I , is regulated by the mitochondrial Ca uniporter channel and is independent of extracellular and cytosolic Na.

Key Points: Ca entry through Ca  release-activated Ca  channels activates numerous cellular responses. Under physiological conditions of weak intracellular Ca buffering, mitochondrial Ca uptake regulates CRAC channel activity. Knockdown of the mitochondrial Ca uniporter channel prevented the development of I in weak buffer but not when strong buffer was used instead.

The Allergen Der p3 from House Dust Mite Stimulates Store-Operated Ca Channels and Mast Cell Migration through PAR4 Receptors.

The house dust mite is the principal source of perennial aeroallergens in man. How these allergens activate innate and adaptive immunity is unclear, and therefore, there are no therapies targeting mite allergens. Here, we show that house dust mite extract activates store-operated Ca channels, a common signaling module in numerous cell types in the lung.

Sequential forward and reverse transport of the Na Ca exchanger generates Ca oscillations within mitochondria.

Mitochondrial Ca homoeostasis regulates aerobic metabolism and cell survival. Ca flux into mitochondria is mediated by the mitochondrial calcium uniporter (MCU) channel whereas Ca export is often through an electrogenic Na-Ca exchanger. Here, we report remarkable functional versatility in mitochondrial Na-Ca exchange under conditions where mitochondria are depolarised.

Regulation of CRAC channels by Ca-dependent inactivation.

CRAC channels are a major route for Ca influx in eukaryotic cells. The channels show prominent Ca-dependent inactivation through two spatially and temporally distinct mechanisms: fast inactivation, which develops over milliseconds and is triggered by Ca near the mouth of the channel and slow inactivation, which arises over tens of seconds and requires a rise in global cytosolic Ca. Slow inactivation is controlled physiologically by Ca uptake into mitochondria through the MCU.

Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca Signals.

Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes. How closely related coexpressed transcription factors are differentially activated remains unclear. Here, we show that two Ca-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP and Ca signals for physiologically sustained activation.

Spatial Ca profiling: decrypting the universal cytosolic Ca oscillation.

Stimulation of cell-surface receptors that couple to phospholipase C to generate the second messenger inositol trisphosphate often evokes repetitive oscillations in cytosolic Ca . Signalling information is encoded in both the amplitude and frequency of the Ca spikes. Recent studies have revealed that the spatial profile of the oscillation also imparts signalling power; Ca microdomains near store-operated CRAC channels in the plasma membrane and inositol trisphosphate-gated channels in the endoplasmic reticulum both signal to distinct downstream targets.