Review: Structure and Activation Mechanisms of CRAC Channels

Butorac, Carmen; Křížová, Adéla; Derler, Isabella

doi:10.1007/978-3-030-12457-1_23

Cited by 30 publications

(41 citation statements)

References 229 publications

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“…4A). In the presence of STIM1, all mutants reach comparable levels of V rev as CRAC and STIM1/Orai1 mediated currents (Butorac et al 2018; Derler et al 2013a; McNally et al 2012, 2013) (Fig. 4B).…”

Section: Introductionmentioning

confidence: 84%

“…Only Orai1 V102A and Orai1 H134A show an enhancement of I DVF compared to I Ca2+ (Fig. 3A) (Butorac et al 2018). The reason for these distinct ratios is probably an altered pore diameter.…”

Section: Introductionmentioning

confidence: 86%

“…Orai1 F136S, Orai1 P245L) and (3) Orai hinge mutants (Orai1 ANSGA) (Derler et al 2018) (Fig. 4A) (Butorac et al 2018).…”

Section: Introductionunclassified

“…Gained knowledge provides the basis for the development of novel therapeutical approaches of diseases that are associated with the STIM1 and Orai proteins. Currently, the function and the unique biophysical characteristics of these channels are well understood (Butorac et al 2018; Derler et al 2016a). Additionally, milestones have been reached in resolving these proteins at a structural level (Hou et al 2012, 2018; Stathopulos et al 2008, 2013; Yang et al 2012; Zheng et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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Critical parameters maintaining authentic CRAC channel hallmarks

2019

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Ca 2+ ions represent versatile second messengers that regulate a huge diversity of processes throughout the cell's life. One prominent Ca 2+ entry pathway into the cell is the Ca 2+ release-activated Ca 2+ (CRAC) ion channel. It is fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM1) and Orai. STIM1 is a Ca 2+ sensor located in the membrane of the endoplasmic reticulum, and Orai, a highly Ca 2+ selective ion channel embedded in the plasma membrane. Ca 2+ store-depletion leads initially to the activation of STIM1 which subsequently activates Orai channels via direct binding. Authentic CRAC channel hallmarks and biophysical characteristics include high Ca 2+ selectivity with a reversal potential in the range of + 50 mV, small unitary conductance, fast Ca 2+-dependent inactivation and enhancements in currents upon the switch from a Na +-containing divalent-free to a Ca 2+-containing solution. This review provides an overview on the critical determinants and structures within the STIM1 and Orai proteins that establish these prominent CRAC channel characteristics.

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Section: Introductionmentioning

confidence: 84%

“…Only Orai1 V102A and Orai1 H134A show an enhancement of I DVF compared to I Ca2+ (Fig. 3A) (Butorac et al 2018). The reason for these distinct ratios is probably an altered pore diameter.…”

Section: Introductionmentioning

confidence: 86%

“…Orai1 F136S, Orai1 P245L) and (3) Orai hinge mutants (Orai1 ANSGA) (Derler et al 2018) (Fig. 4A) (Butorac et al 2018).…”

Section: Introductionunclassified

Section: Introductionmentioning

confidence: 99%

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Critical parameters maintaining authentic CRAC channel hallmarks

2019

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“…This is logical because Ca 2+ release is extremely dynamic in ICC, and it is likely that store Ca 2+ would be depleted without an effective recovery mechanism. SOCE depends upon the expression of Orai channels and the ER delimited activator of Orai, STIM, that senses ER Ca 2+ and binds to and activates Orai channels when Ca 2+ depletion of the ER occurs [102]. STIM and Orai are expressed in colonic ICC [103].…”

Section: Discussionmentioning

confidence: 99%

Ca²⁺signaling driving pacemaker activity in submucosal interstitial cells of Cajal in the colon

Baker

Leigh

Yturriaga

et al. 2020

Preprint

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Interstitial cells of Cajal (ICC) generate pacemaker activity responsible for phasic contractions in colonic segmentation and peristalsis. ICC along the submucosal border (ICC-SM) contributing to mixing and more complex patterns of colonic motility. We show the complex patterns of Ca2+ signaling in ICC-SM and the relationship between ICC-SM Ca2+ transients and activation of SMCs using optogenetic tools. ICC-SM displayed rhythmic firing of Ca2+ transients ~15 cpm and paced adjacent SMCs. The majority of spontaneous activity occurred in regular Ca2+ transients clusters (CTCs) that propagated through the network. CTCs were organized and dependent upon Ca2+ entry through voltage-dependent Ca2+ conductances, L- and T-type Ca2+ channels. Removal of Ca2+ from the external solution abolished CTCs. Ca2+ release mechanisms reduced the duration and amplitude of Ca2+ transients but did not block CTCs. These data reveal how colonic pacemaker ICC-SM exhibit complex Ca2+ firing patterns and drive smooth muscle activity and overall colonic contractions.

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Defects in the STIM1 SOARα2 domain affect multiple steps in the CRAC channel activation cascade

Höglinger

Grabmayr

Maltan

et al. 2021

Cell. Mol. Life Sci.

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The calcium release-activated calcium (CRAC) channel consists of STIM1, a Ca2+ sensor in the endoplasmic reticulum (ER), and Orai1, the Ca2+ ion channel in the plasma membrane. Ca2+ store depletion triggers conformational changes and oligomerization of STIM1 proteins and their direct interaction with Orai1. Structural alterations include the transition of STIM1 C-terminus from a folded to an extended conformation thereby exposing CAD (CRAC activation domain)/SOAR (STIM1-Orai1 activation region) for coupling to Orai1. In this study, we discovered that different point mutations of F394 in the small alpha helical segment (STIM1 α2) within the CAD/SOAR apex entail a rich plethora of effects on diverse STIM1 activation steps. An alanine substitution (STIM1 F394A) destabilized the STIM1 quiescent state, as evident from its constitutive activity. Single point mutation to hydrophilic, charged amino acids (STIM1 F394D, STIM1 F394K) impaired STIM1 homomerization and subsequent Orai1 activation. MD simulations suggest that their loss of homomerization may arise from altered formation of the CC1α1-SOAR/CAD interface and potential electrostatic interactions with lipid headgroups in the ER membrane. Consistent with these findings, we provide experimental evidence that the perturbing effects of F394D depend on the distance of the apex from the ER membrane. Taken together, our results suggest that the CAD/SOAR apex is in the immediate vicinity of the ER membrane in the STIM1 quiescent state and that different mutations therein can impact the STIM1/Orai1 activation cascade in various manners. Graphic abstract Legend: Upon intracellular Ca2+ store depletion of the endoplasmic reticulum (ER), Ca2+ dissociates from STIM1. As a result, STIM1 adopts an elongated conformation and elicits Ca2+ influx from the extracellular matrix (EM) into the cell due to binding to and activation of Ca2+-selective Orai1 channels (left). The effects of three point mutations within the SOARα2 domain highlight the manifold roles of this region in the STIM1/Orai1 activation cascade: STIM1 F394A is active irrespective of the intracellular ER Ca2+ store level, but activates Orai1 channels to a reduced extent (middle). On the other hand, STIM1 F394D/K cannot adopt an elongated conformation upon Ca2+ store-depletion due to altered formation of the CC1α1-SOAR/CAD interface and/or electrostatic interaction of the respective side-chain charge with corresponding opposite charges on lipid headgroups in the ER membrane (right).

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Review: Structure and Activation Mechanisms of CRAC Channels

Cited by 30 publications

References 229 publications

Critical parameters maintaining authentic CRAC channel hallmarks

Critical parameters maintaining authentic CRAC channel hallmarks

Ca²⁺signaling driving pacemaker activity in submucosal interstitial cells of Cajal in the colon

Defects in the STIM1 SOARα2 domain affect multiple steps in the CRAC channel activation cascade

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Review: Structure and Activation Mechanisms of CRAC Channels

Cited by 30 publications

References 229 publications

Critical parameters maintaining authentic CRAC channel hallmarks

Critical parameters maintaining authentic CRAC channel hallmarks

Ca2+signaling driving pacemaker activity in submucosal interstitial cells of Cajal in the colon

Defects in the STIM1 SOARα2 domain affect multiple steps in the CRAC channel activation cascade

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Ca²⁺signaling driving pacemaker activity in submucosal interstitial cells of Cajal in the colon