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Review
. 2023 Feb 10:85:217-243.
doi: 10.1146/annurev-physiol-032122-104610. Epub 2022 Oct 6.

Endoplasmic Reticulum-Plasma Membrane Junctions as Sites of Depolarization-Induced Ca2+ Signaling in Excitable Cells

Rose E Dixon  1 , James S Trimmer  1
Affiliations
Review

Endoplasmic Reticulum-Plasma Membrane Junctions as Sites of Depolarization-Induced Ca2+ Signaling in Excitable Cells

Rose E Dixon et al. Annu Rev Physiol. .

Abstract

Membrane contact sites between endoplasmic reticulum (ER) and plasma membrane (PM), or ER-PM junctions, are found in all eukaryotic cells. In excitable cells they play unique roles in organizing diverse forms of Ca2+ signaling as triggered by membrane depolarization. ER-PM junctions underlie crucial physiological processes such as excitation-contraction coupling, smooth muscle contraction and relaxation, and various forms of activity-dependent signaling and plasticity in neurons. In many cases the structure and molecular composition of ER-PM junctions in excitable cells comprise important regulatory feedback loops linking depolarization-induced Ca2+ signaling at these sites to the regulation of membrane potential. Here, we describe recent findings on physiological roles and molecular composition of native ER-PM junctions in excitable cells. We focus on recent studies that provide new insights into canonical forms of depolarization-induced Ca2+ signaling occurring at junctional triads and dyads of striated muscle, as well as the diversity of ER-PM junctions in these cells and in smooth muscle and neurons.

Keywords: cardiac muscle; ion channel; membrane contact sites; neuron; second messenger; skeletal muscle; smooth muscle.

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Figures

Figure 1.
Figure 1.. SR-PM junctions as platforms for depolarization-induced Ca2+ signaling in muscle.
a) Depiction of a skeletal muscle triad with the typical SR-TT-SR arrangement where t-tubule localized CaV1.1 channels (blue) physically interact with jSR-localized RyR1 (teal) to orchestrate Ca2+ signaling that leads to contraction during AP-induced depolarizations. Triadic proteins JPH1 and JPH2 (dark blue) tether the junctions while triad morphology is supported by MG29 (dark red) and BIN1 (grey). b) Illustration of a cardiac muscle dyad showing CaV1.2 channels (light link) within nanometer proximity of SR-localized RyR2 (teal). This arrangement facilitates CICR and myocardial contraction. Dyadic proteins NEXN (orange), BIN1 (grey) and JPH2 (dark blue) play roles in dyad regulation, membrane folding, and tethering respectively. c) Cartoon of smooth muscle peripheral couplings, focusing on those between the caveolar PM and peripheral SR. (i) A MCS containing PM BK channels (gold) and ER RyR2 (teal) allows for BK channel activation by RyR2-mediated Ca2+ release, leading to reduced CaV1.2 (pink) activity and favoring smooth muscle relaxation. (ii) ER-PM junctions at which activation of PM TRPM4 channels (purple) by Ca2+ release from closely associated ER IP3Rs (dark green) triggers membrane depolarization that enhances CaV1.2 (pink) activity favoring smooth muscle contraction. (iii) A MCS containing PM Ca2+ activated Cl− channels (red) that are activated by Ca2+ release from nearby ER IP3R (green) or RyR (teal) leads to membrane depolarization that activates Cav1.2 (pink) L-type Ca2+ channels leading to smooth muscle contraction. Figure created with Biorender.com. CICR: Ca2+-induced Ca2+ release; ER: endoplasmic reticulum; ER-PM: endoplasmic reticulum-plasma membrane: jSR: junctional sarcoplasmic reticulum; MCS: membrane contact site; SR: sarcoplasmic reticulum; STIC: spontaneous transient inward currents mediated by Ca2+ activated Cl− channels; STOC: spontaneous transient outward currents mediated by Ca2+ activated K+ channels; TT: t-tubule.
Figure 2.
Figure 2.. Neuronal ER-PM junctions as platforms for depolarization-induced Ca2+ signaling.
a) KV2 containing ER-PM junctions in hippocampal pyramidal neurons comprise PM KV2.1 (or KV2.2) channels (light blue) in association with ER VAP proteins (black). KV2 channels recruit PM CaV1.2 L-type Ca2+ channels (pink) leading to their increased clustering that enhances their activity and brings them into close spatial and functional association with ER RyRs (teal) facilitating depolarization-induced CICR and downstream Ca2+ signaling pathways including excitation-transcription coupling. b) PM CaV2.1 voltage-gated Ca2+ channels (light green) are localized at ER-PM junctions in cartwheel interneurons of dorsal cochlear nucleus bringing them into close spatial and functional association with ER RyRs (teal) facilitating depolarization-induced CICR that activates Ca2+-activated BK channels (light gold) to control AP firing patterns. c) In hippocampal neurons, CaV1.3 LTCCs (light pink) are localized at ER-PM junctions stabilized by JPH3 and JPH4 (dark blue) bringing them into close spatial and functional association with ER RyRs (teal) facilitating depolarization-induced CICR that activates Ca2+-activated IK channels (orange) to generate the slow AHP. Figure created with Biorender.com. AHP: afterhyperpolarization; AP: action potential; CICR: Ca2+-induced Ca2+ release; ER: endoplasmic reticulum; ER-PM: endoplasmic reticulum-plasma membrane; PM: plasma membrane.
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References

    1. Prinz WA, Toulmay A, Balla T. 2020. The functional universe of membrane contact sites. Nat Rev Mol Cell Biol 21:7–24 - PMC - PubMed
    1. Henne WM, Liou J, Emr SD. 2015. Molecular mechanisms of inter-organelle ER-PM contact sites. Curr Opin Cell Biol 35:123–30 - PubMed
    1. Stefan CJ. 2020. Endoplasmic reticulum-plasma membrane contacts: Principals of phosphoinositide and calcium signaling. Curr Opin Cell Biol 63:125–34 - PubMed
    1. Burgoyne T, Patel S, Eden ER. 2015. Calcium signaling at ER membrane contact sites. Biochim Biophys Acta 1853:2012–7 - PubMed
    1. Balla T 2018. Ca(2+) and lipid signals hold hands at endoplasmic reticulum-plasma membrane contact sites. J Physiol 596:2709–16 - PMC - PubMed

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