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14 pages, 3613 KiB

Open AccessFeature PaperArticle

An Alternatively Translated Connexin 43 Isoform, GJA1-11k, Localizes to the Nucleus and Can Inhibit Cell Cycle Progression

by Irina Epifantseva, Shaohua Xiao, Rachel E. Baum, André G. Kléber, TingTing Hong and Robin M. Shaw

Biomolecules 2020, 10(3), 473; https://doi.org/10.3390/biom10030473 - 20 Mar 2020

Cited by 21 | Viewed by 3840

Abstract

Connexin 43 (Cx43) is a gap junction protein that assembles at the cell border to form intercellular gap junction (GJ) channels which allow for cell–cell communication by facilitating the rapid transmission of ions and other small molecules between adjacent cells. Non-canonical roles of [...] Read more.

Connexin 43 (Cx43) is a gap junction protein that assembles at the cell border to form intercellular gap junction (GJ) channels which allow for cell–cell communication by facilitating the rapid transmission of ions and other small molecules between adjacent cells. Non-canonical roles of Cx43, and specifically its C-terminal domain, have been identified in the regulation of Cx43 trafficking, mitochondrial preconditioning, cell proliferation, and tumor formation, yet the mechanisms are still being explored. It was recently identified that up to six truncated isoforms of Cx43 are endogenously produced via alternative translation from internal start codons in addition to full length Cx43, all from the same mRNA produced by the gene GJA1. GJA1-11k, the 11kDa alternatively translated isoform of Cx43, does not have a known role in the formation of gap junction channels, and little is known about its function. Here, we report that over expressed GJA1-11k, unlike the other five truncated isoforms, preferentially localizes to the nucleus in HEK293FT cells and suppresses cell growth by limiting cell cycle progression from the G₀/G₁ phase to the S phase. Furthermore, these functions are independent of the channel-forming full-length Cx43 isoform. Understanding the apparently unique role of GJA1-11k and its generation in cell cycle regulation may uncover a new target for affecting cell growth in multiple disease models. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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Review

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16 pages, 2718 KiB

Open AccessReview

Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients

by Makoto Ono, Don E. Burgess, Elizabeth A. Schroder, Claude S. Elayi, Corey L. Anderson, Craig T. January, Bin Sun, Kalyan Immadisetty, Peter M. Kekenes-Huskey and Brian P. Delisle

Biomolecules 2020, 10(8), 1144; https://doi.org/10.3390/biom10081144 - 4 Aug 2020

Cited by 27 | Viewed by 5540

Abstract

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) [...] Read more.

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the KCNH2 gene (also known as the human ether-à-go-go-related gene or hERG). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the KCNH2-encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which KCNH2 missense variants confer a high-risk for LQT2. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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22 pages, 8209 KiB

Open AccessEditor’s ChoiceReview

Cell-Adhesion Properties of β-Subunits in the Regulation of Cardiomyocyte Sodium Channels

by Samantha C. Salvage, Christopher L.-H. Huang and Antony P. Jackson

Biomolecules 2020, 10(7), 989; https://doi.org/10.3390/biom10070989 - 1 Jul 2020

Cited by 14 | Viewed by 5419

Abstract

Voltage-gated sodium (Nav) channels drive the rising phase of the action potential, essential for electrical signalling in nerves and muscles. The Nav channel α-subunit contains the ion-selective pore. In the cardiomyocyte, Nav1.5 is the main Nav channel α-subunit isoform, with a smaller expression [...] Read more.

Voltage-gated sodium (Nav) channels drive the rising phase of the action potential, essential for electrical signalling in nerves and muscles. The Nav channel α-subunit contains the ion-selective pore. In the cardiomyocyte, Nav1.5 is the main Nav channel α-subunit isoform, with a smaller expression of neuronal Nav channels. Four distinct regulatory β-subunits (β1–4) bind to the Nav channel α-subunits. Previous work has emphasised the β-subunits as direct Nav channel gating modulators. However, there is now increasing appreciation of additional roles played by these subunits. In this review, we focus on β-subunits as homophilic and heterophilic cell-adhesion molecules and the implications for cardiomyocyte function. Based on recent cryogenic electron microscopy (cryo-EM) data, we suggest that the β-subunits interact with Nav1.5 in a different way from their binding to other Nav channel isoforms. We believe this feature may facilitate trans-cell-adhesion between β1-associated Nav1.5 subunits on the intercalated disc and promote ephaptic conduction between cardiomyocytes. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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33 pages, 1432 KiB

Open AccessReview

Assistance for Folding of Disease-Causing Plasma Membrane Proteins

by Karina Juarez-Navarro, Victor M. Ayala-Garcia, Estela Ruiz-Baca, Ivan Meneses-Morales, Jose Luis Rios-Banuelos and Angelica Lopez-Rodriguez

Biomolecules 2020, 10(5), 728; https://doi.org/10.3390/biom10050728 - 7 May 2020

Cited by 3 | Viewed by 4427

Abstract

An extensive catalog of plasma membrane (PM) protein mutations related to phenotypic diseases is associated with incorrect protein folding and/or localization. These impairments, in addition to dysfunction, frequently promote protein aggregation, which can be detrimental to cells. Here, we review PM protein processing, [...] Read more.

An extensive catalog of plasma membrane (PM) protein mutations related to phenotypic diseases is associated with incorrect protein folding and/or localization. These impairments, in addition to dysfunction, frequently promote protein aggregation, which can be detrimental to cells. Here, we review PM protein processing, from protein synthesis in the endoplasmic reticulum to delivery to the PM, stressing the main repercussions of processing failures and their physiological consequences in pathologies, and we summarize the recent proposed therapeutic strategies to rescue misassembled proteins through different types of chaperones and/or small molecule drugs that safeguard protein quality control and regulate proteostasis. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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10 pages, 1111 KiB

Open AccessReview

Mechanisms and Alterations of Cardiac Ion Channels Leading to Disease: Role of Ankyrin-B in Cardiac Function

by Holly C. Sucharski, Emma K. Dudley, Caullin B. R. Keith, Mona El Refaey, Sara N. Koenig and Peter J. Mohler

Biomolecules 2020, 10(2), 211; https://doi.org/10.3390/biom10020211 - 31 Jan 2020

Cited by 15 | Viewed by 3986

Abstract

Ankyrin-B (encoded by ANK2), originally identified as a key cytoskeletal-associated protein in the brain, is highly expressed in the heart and plays critical roles in cardiac physiology and cell biology. In the heart, ankyrin-B plays key roles in the targeting and localization [...] Read more.

Ankyrin-B (encoded by ANK2), originally identified as a key cytoskeletal-associated protein in the brain, is highly expressed in the heart and plays critical roles in cardiac physiology and cell biology. In the heart, ankyrin-B plays key roles in the targeting and localization of key ion channels and transporters, structural proteins, and signaling molecules. The role of ankyrin-B in normal cardiac function is illustrated in animal models lacking ankyrin-B expression, which display significant electrical and structural phenotypes and life-threatening arrhythmias. Further, ankyrin-B dysfunction has been associated with cardiac phenotypes in humans (now referred to as “ankyrin-B syndrome”) including sinus node dysfunction, heart rate variability, atrial fibrillation, conduction block, arrhythmogenic cardiomyopathy, structural remodeling, and sudden cardiac death. Here, we review the diverse roles of ankyrin-B in the vertebrate heart with a significant focus on ankyrin-B-linked cell- and molecular-pathways and disease. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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13 pages, 3029 KiB

Open AccessReview

Trafficking of Stretch-Regulated TRPV2 and TRPV4 Channels Inferred Through Interactomics

by Pau Doñate-Macián, Jennifer Enrich-Bengoa, Irene R. Dégano, David G. Quintana and Alex Perálvarez-Marín

Biomolecules 2019, 9(12), 791; https://doi.org/10.3390/biom9120791 - 27 Nov 2019

Cited by 8 | Viewed by 4412

Abstract

Transient receptor potential cation channels are emerging as important physiological and therapeutic targets. Within the vanilloid subfamily, transient receptor potential vanilloid 2 (TRPV2) and 4 (TRPV4) are osmo- and mechanosensors becoming critical determinants in cell structure and activity. However, knowledge is scarce regarding [...] Read more.

Transient receptor potential cation channels are emerging as important physiological and therapeutic targets. Within the vanilloid subfamily, transient receptor potential vanilloid 2 (TRPV2) and 4 (TRPV4) are osmo- and mechanosensors becoming critical determinants in cell structure and activity. However, knowledge is scarce regarding how TRPV2 and TRPV4 are trafficked to the plasma membrane or specific organelles to undergo quality controls through processes such as biosynthesis, anterograde/retrograde trafficking, and recycling. This review lists and reviews a subset of protein–protein interactions from the TRPV2 and TRPV4 interactomes, which is related to trafficking processes such as lipid metabolism, phosphoinositide signaling, vesicle-mediated transport, and synaptic-related exocytosis. Identifying the protein and lipid players involved in trafficking will improve the knowledge on how these stretch-related channels reach specific cellular compartments. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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Graphical abstract

15 pages, 2051 KiB

Open AccessReview

Disease Associated Mutations in K_IR Proteins Linked to Aberrant Inward Rectifier Channel Trafficking

by Eva-Maria Zangerl-Plessl, Muge Qile, Meye Bloothooft, Anna Stary-Weinzinger and Marcel A. G. van der Heyden

Biomolecules 2019, 9(11), 650; https://doi.org/10.3390/biom9110650 - 25 Oct 2019

Cited by 20 | Viewed by 4029

Abstract

The ubiquitously expressed family of inward rectifier potassium (K_IR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Channel mutations associate with a variety of severe human diseases and syndromes, affecting many organ systems including the [...] Read more.

The ubiquitously expressed family of inward rectifier potassium (K_IR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Channel mutations associate with a variety of severe human diseases and syndromes, affecting many organ systems including the central and peripheral neural system, heart, kidney, pancreas, and skeletal muscle. A number of mutations associate with altered ion channel expression at the plasma membrane, which might result from defective channel trafficking. Trafficking involves cellular processes that transport ion channels to and from their place of function. By alignment of all K_IR channels, and depicting the trafficking associated mutations, three mutational hotspots were identified. One localized in the transmembrane-domain 1 and immediately adjacent sequences, one was found in the G-loop and Golgi-export domain, and the third one was detected at the immunoglobulin-like domain. Surprisingly, only few mutations were observed in experimentally determined Endoplasmic Reticulum (ER)exit-, export-, or ER-retention motifs. Structural mapping of the trafficking defect causing mutations provided a 3D framework, which indicates that trafficking deficient mutations form clusters. These “mutation clusters” affect trafficking by different mechanisms, including protein stability. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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15 pages, 1988 KiB

Open AccessReview

Trafficking and Function of the Voltage-Gated Sodium Channel β2 Subunit

by Eric Cortada, Ramon Brugada and Marcel Verges

Biomolecules 2019, 9(10), 604; https://doi.org/10.3390/biom9100604 - 13 Oct 2019

Cited by 11 | Viewed by 3893

Abstract

The voltage-gated sodium channel is vital for cardiomyocyte function, and consists of a protein complex containing a pore-forming α subunit and two associated β subunits. A fundamental, yet unsolved, question is to define the precise function of β subunits. While their location in [...] Read more.

The voltage-gated sodium channel is vital for cardiomyocyte function, and consists of a protein complex containing a pore-forming α subunit and two associated β subunits. A fundamental, yet unsolved, question is to define the precise function of β subunits. While their location in vivo remains unclear, large evidence shows that they regulate localization of α and the biophysical properties of the channel. The current data support that one of these subunits, β2, promotes cell surface expression of α. The main α isoform in an adult heart is Na_V1.5, and mutations in SCN5A, the gene encoding Na_V1.5, often lead to hereditary arrhythmias and sudden death. The association of β2 with cardiac arrhythmias has also been described, which could be due to alterations in trafficking, anchoring, and localization of Na_V1.5 at the cardiomyocyte surface. Here, we will discuss research dealing with mechanisms that regulate β2 trafficking, and how β2 could be pivotal for the correct localization of Na_V1.5, which influences cellular excitability and electrical coupling of the heart. Moreover, β2 may have yet to be discovered roles on cell adhesion and signaling, implying that diverse defects leading to human disease may arise due to β2 mutations. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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