Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

Gambardella, Jessica; Lombardi, Angela; Morelli, Marco Bruno; Ferrara, John J.; Santulli, Gaetano

doi:10.3390/jcm9041096

Cited by 23 publications

(18 citation statements)

References 129 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The deletion of the nearby residue K2603 (K2563 in human IP 3 R1) at the cytosolic extension of TM6 has been linked to Gillespie Syndrome and causes dysfunctional IP 3 R1 channels that are unable to release Ca 2+ (Fig. 5) 20,21 . This deletion would effectively shorten the length of TM6 likely altering the intermolecular contacts of the ILD/LNK nexus with the TMDs.…”

Section: Resultsmentioning

confidence: 99%

Cryo-EM structure of type 1 IP3R channel in a lipid bilayer

et al. 2021

View full text Add to dashboard Cite

Type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) is the predominant Ca2+-release channel in neurons. IP3R1 mediates Ca2+ release from the endoplasmic reticulum into the cytosol and thereby is involved in many physiological processes. Here, we present the cryo-EM structures of full-length rat IP3R1 reconstituted in lipid nanodisc and detergent solubilized in the presence of phosphatidylcholine determined in ligand-free, closed states by single-particle electron cryo-microscopy. Notably, both structures exhibit the well-established IP3R1 protein fold and reveal a nearly complete representation of lipids with similar locations of ordered lipids bound to the transmembrane domains. The lipid-bound structures show improved features that enabled us to unambiguously build atomic models of IP3R1 including two membrane associated helices that were not previously resolved in the TM region. Our findings suggest conserved locations of protein-bound lipids among homotetrameric ion channels that are critical for their structural and functional integrity despite the diversity of structural mechanisms for their gating.

show abstract

Section: Resultsmentioning

confidence: 99%

Cryo-EM structure of type 1 IP3R channel in a lipid bilayer

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Opening of the IP 3 Rs results in the rapid release of Ca 2+ from the ER into the cytoplasm triggering diverse signaling cascades to regulate physiological processes such as learning, fertilization, gene expression, and apoptosis. Dysfunctional IP 3 Rs cause abnormal Ca 2+ signaling and are associated with many diseases, including diabetes, cancer, and neurological disorders 4,5 . There are three IP 3 R subtypes (IP 3 R-1, −2, and −3) that share 60-70% sequence identity, form homo- or hetero-tetramers, exhibit different spatial expression profiles, and are involved in different signaling pathways 1-3 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for activation and gating of IP₃ receptors

Schmitz

Takahashi

Karakaş

2021

Preprint

View full text Add to dashboard Cite

Calcium (Ca2+) is a universal and versatile cellular messenger used to regulate numerous cellular processes in response to external or internal stimuli. A pivotal component of the Ca2+ signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs), which mediate Ca2+ release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca2+ concentrations. IP3Rs are activated by IP3 and Ca2+, inhibited by Ca2+ at high concentrations, and potentiated by ATP1-3. However, the underlying molecular mechanisms are unclear due to the lack of structures in the active conformation. Here we report cryo-electron microscopy (cryo-EM) structures of human type-3 IP3R in multiple gating conformations; IP3-ATP bound pre-active states with closed channels, IP3-ATP-Ca2+ bound active state with an open channel, and IP3-ATP-Ca2+ bound inactive state with a closed channel. The structures demonstrate how IP3-induced conformational changes prime the receptor for activation by Ca2+, how Ca2+ binding leads to channel opening, and how ATP modulates the activity, providing insights into the long-sought questions regarding the molecular mechanism of the receptor activation and gating.

show abstract

“…Intracellular Ca 2+ release channels comprise one subset of ion channels; these include the ryanodine receptor (RyR) and inositol 1,4,5-triphosphosphate (IP 3 ) receptor (IP 3 R) channels, both of which are localized to the ER and SR. RyR channels, which are activated by elevated [Ca 2+ ] i or protein signaling, and IP 3 R channels, which are activated by IP 3 binding, release Ca 2+ from the ER and SR. Through [Ca 2+ ] i signaling, these two channel types modulate muscle contraction and nerve impulse transmission [9,10]. Abberant Ca 2+ transport from the ER or SR to the cytosol may elevate [Ca 2+ ] m and consequently induce mitochondrial dysfunction [11,12].…”

mentioning

confidence: 99%

Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells

Zhai

Líšková

Kubatka

et al. 2020

IJMS

View full text Add to dashboard Cite

Intracellular calcium (Ca2+) concentration ([Ca2+]i) is a key determinant of cell fate and is implicated in carcinogenesis. Membrane ion channels are structures through which ions enter or exit the cell, depending on the driving forces. The opening of transient receptor potential vanilloid 1 (TRPV1) ligand-gated ion channels facilitates transmembrane Ca2+ and Na+ entry, which modifies the delicate balance between apoptotic and proliferative signaling pathways. Proliferation is upregulated through two mechanisms: (1) ATP binding to the G-protein-coupled receptor P2Y2, commencing a kinase signaling cascade that activates the serine-threonine kinase Akt, and (2) the transactivation of the epidermal growth factor receptor (EGFR), leading to a series of protein signals that activate the extracellular signal-regulated kinases (ERK) 1/2. The TRPV1-apoptosis pathway involves Ca2+ influx and efflux between the cytosol, mitochondria, and endoplasmic reticulum (ER), the release of apoptosis-inducing factor (AIF) and cytochrome c from the mitochondria, caspase activation, and DNA fragmentation and condensation. While proliferative mechanisms are typically upregulated in cancerous tissues, shifting the balance to favor apoptosis could support anti-cancer therapies. TRPV1, through [Ca2+]i signaling, influences cancer cell fate; therefore, the modulation of the TRPV1-enforced proliferation–apoptosis balance is a promising avenue in developing anti-cancer therapies and overcoming cancer drug resistance. As such, this review characterizes and evaluates the role of TRPV1 in cell death and survival, in the interest of identifying mechanistic targets for drug discovery.

show abstract

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

Cited by 23 publications

References 129 publications

Cryo-EM structure of type 1 IP3R channel in a lipid bilayer

Cryo-EM structure of type 1 IP3R channel in a lipid bilayer

Structural basis for activation and gating of IP₃ receptors

Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells

Contact Info

Product

Resources

About

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

Cited by 23 publications

References 129 publications

Cryo-EM structure of type 1 IP3R channel in a lipid bilayer

Cryo-EM structure of type 1 IP3R channel in a lipid bilayer

Structural basis for activation and gating of IP3 receptors

Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells

Contact Info

Product

Resources

About

Structural basis for activation and gating of IP₃ receptors