Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling

Abstract

Ca²⁺ is a ubiquitous intracellular messenger that controls diverse cellular functions but can become toxic and cause cell death. Selective control of specific targets depends on spatiotemporal patterning of the calcium signal and decoding it by multiple, tunable, and often strategically positioned Ca²⁺-sensing elements. Ca²⁺ is detected by specialized motifs on proteins that have been biochemically characterized decades ago. However, the field of Ca²⁺ sensing has been reenergized by recent progress in fluorescent technology, genetics, and cryo-EM. These approaches exposed local Ca²⁺-sensing mechanisms inside organelles and at the organellar interfaces, revealed how Ca²⁺ binding might work to open some channels, and identified human mutations and disorders linked to a variety of Ca²⁺-sensing proteins. Here we attempt to place these new developments in the context of intracellular calcium homeostasis and signaling.

Keywords: ER; IP(3) receptor; MICU1; Miro1; STIM1; endoplasmic reticulum; mitochondria.

Figure 1. A schematic representation of the Ca²⁺-regulated proteins involved in: cellular Ca²⁺ homeostasis and signaling

A) [Ca²⁺] in the different cellular compartments is indicated by a green scale ranging from 100nM (light green) to 1mM (dark green). The Ca²⁺-transporting systems that increase [Ca²⁺]_c are highlighted in blue, and in red those which decrease [Ca²⁺]_c. The green arrows indicate the positive and negative feedback effects of [Ca²⁺]_c on the Ca²⁺-transporting systems. B) Cellular processes regulated by calcium signaling are listed in this scheme as well as the main Ca²⁺- regulated proteins involved in each process. In parenthesis are indicated the Ca²⁺-binding motifs of the Ca²⁺-regulated proteins, which could belong to: the EF-hand proteins (EF – EF hand domains; CaM – Calmodulin), the annexins or the C2 motif proteins (C2).

Figure 2. Different types of Ca²⁺-dependent regulation of effector's function depending on the localization of Ca²⁺-binding motif

Ca²⁺-binding sites can be present in the effector proteins (A) and thereby regulate their function in a Ca²⁺-dependent manner, or in specialized Ca²⁺-sensing proteins (B – D). These proteins may regulate effector protein activity by Ca²⁺-dependent association (i.e. Ca²⁺-binding proteins, CaBP) (B) or by post-translation modifications (C – D). These modifications are displayed by enzymes that are regulated in a Ca²⁺-dependent manner either because they have a Ca²⁺-binding motif (i.e. Ca²⁺-binding enzymes, CaBEnzyme) (C) or because they are associated with a CaBP (D).

Figure 3. Local calcium signaling is mediated by compartmentalized Ca²⁺-sensors within the cell

A) Scheme visualizing the cellular localization of Ca²⁺-sensors that regulate local function such as store-operated Ca²⁺ entry (SOCE) (B), mitochondrial Ca²⁺ uptake (C) or mitochondrial motility (D). B) SOCE is regulated by STIM1 which senses the ER lumen Ca²⁺ content via its EF-hands. Upon ER Ca²⁺ depletion, STIM1 undergo a Ca²⁺-regulated conformational change that promotes its oligomerization and activation of Orai Ca²⁺ channels. Increase of [Ca²⁺]_c suppresses Ca²⁺ influx by triggering CaM binding to Ora1. C) Mitochondrial Ca²⁺ uptake via MCU is regulated by the Ca²⁺-sensing proteins MICU1 and MICU2. In resting conditions, MICUs interaction with MCU prevent mitochondrial Ca²⁺ uptake. Local Ca²⁺ release by IP3R promotes the MCU pore opening due to a Ca²⁺-regulated conformational change of MICUs. D) Mitochondrial motility along the microtubules is controlled by the Ca²⁺-sensing protein Miro. At low cytoplasmic [Ca²⁺], Miro facilitates the retrograde and anterograde movement of mitochondria through its interaction via Milton/Trak with dynein and kinesin (KIF5), respectively. Upon Ca²⁺-binding to Miro's EF hands due to an increase in [Ca²⁺]_c, mitochondrial motility is suppressed in both directions.