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21 pages, 27284 KiB

Open AccessFeature PaperArticle

Phosphoprotein Phosphatase 1 but Not 2A Activity Modulates Coupled-Clock Mechanisms to Impact on Intrinsic Automaticity of Sinoatrial Nodal Pacemaker Cells

by Syevda Tagirova Sirenko, Ihor Zahanich, Yue Li, Yevgeniya O. Lukyanenko, Alexey E. Lyashkov, Bruce D. Ziman, Kirill V. Tarasov, Antoine Younes, Daniel R. Riordon, Yelena S. Tarasova, Dongmei Yang, Tatiana M. Vinogradova, Victor A. Maltsev and Edward G. Lakatta

Cells 2021, 10(11), 3106; https://doi.org/10.3390/cells10113106 - 10 Nov 2021

Cited by 8 | Viewed by 3044

Abstract

Spontaneous AP (action potential) firing of sinoatrial nodal cells (SANC) is critically dependent on protein kinase A (PKA) and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)-dependent protein phosphorylation, which are required for the generation of spontaneous, diastolic local Ca²⁺ releases (LCRs). Although [...] Read more.

Spontaneous AP (action potential) firing of sinoatrial nodal cells (SANC) is critically dependent on protein kinase A (PKA) and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)-dependent protein phosphorylation, which are required for the generation of spontaneous, diastolic local Ca²⁺ releases (LCRs). Although phosphoprotein phosphatases (PP) regulate protein phosphorylation, the expression level of PPs and phosphatase inhibitors in SANC and the impact of phosphatase inhibition on the spontaneous LCRs and other players of the oscillatory coupled-clock system is unknown. Here, we show that rabbit SANC express both PP1, PP2A, and endogenous PP inhibitors I-1 (PPI-1), dopamine and cyclic adenosine 3′,5′-monophosphate (cAMP)-regulated phosphoprotein (DARPP-32), kinase C-enhanced PP1 inhibitor (KEPI). Application of Calyculin A, (CyA), a PPs inhibitor, to intact, freshly isolated single SANC: (1) significantly increased phospholamban (PLB) phosphorylation (by 2–3-fold) at both CaMKII-dependent Thr¹⁷ and PKA-dependent Ser¹⁶ sites, in a time and concentration dependent manner; (2) increased ryanodine receptor (RyR) phosphorylation at the Ser²⁸⁰⁹ site; (3) substantially increased sarcoplasmic reticulum (SR) Ca²⁺ load; (4) augmented L-type Ca²⁺ current amplitude; (5) augmented LCR’s characteristics and decreased LCR period in intact and permeabilized SANC, and (6) increased the spontaneous basal AP firing rate. In contrast, the selective PP2A inhibitor okadaic acid (100 nmol/L) had no significant effect on spontaneous AP firing, LCR parameters, or PLB phosphorylation. Application of purified PP1 to permeabilized SANC suppressed LCR, whereas purified PP2A had no effect on LCR characteristics. Our numerical model simulations demonstrated that PP inhibition increases AP firing rate via a coupled-clock mechanism, including respective increases in the SR Ca²⁺ pumping rate, L-type Ca²⁺ current, and Na⁺/Ca²⁺-exchanger current. Thus, PP1 and its endogenous inhibitors modulate the basal spontaneous firing rate of cardiac pacemaker cells by suppressing SR Ca²⁺ cycling protein phosphorylation, the SR Ca²⁺ load and LCRs, and L-type Ca²⁺ current. Full article

(This article belongs to the Special Issue Cell Biology in the United States: Latest Advances and Perspectives)

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19 pages, 4251 KiB

Open AccessFeature PaperArticle

CRMP2 Is Involved in Regulation of Mitochondrial Morphology and Motility in Neurons

by Tatiana Brustovetsky, Rajesh Khanna and Nickolay Brustovetsky

Cells 2021, 10(10), 2781; https://doi.org/10.3390/cells10102781 - 17 Oct 2021

Cited by 8 | Viewed by 3859

Abstract

Regulation of mitochondrial morphology and motility is critical for neurons, but the exact mechanisms are unclear. Here, we demonstrate that these mechanisms may involve collapsin response mediator protein 2 (CRMP2). CRMP2 is attached to neuronal mitochondria and binds to dynamin-related protein 1 (Drp1), [...] Read more.

Regulation of mitochondrial morphology and motility is critical for neurons, but the exact mechanisms are unclear. Here, we demonstrate that these mechanisms may involve collapsin response mediator protein 2 (CRMP2). CRMP2 is attached to neuronal mitochondria and binds to dynamin-related protein 1 (Drp1), Miro 2, and Kinesin 1 light chain (KLC1). Treating neurons with okadaic acid (OA), an inhibitor of phosphatases PP1 and PP2A, resulted in increased CRMP2 phosphorylation at Thr509/514, Ser522, and Thr555, and augmented Drp1 phosphorylation at Ser616. The CRMP2-binding small molecule (S)-lacosamide ((S)-LCM) prevented an OA-induced increase in CRMP2 phosphorylation at Thr509/514 and Ser522 but not at Thr555, and also failed to alleviate Drp1 phosphorylation. The increased CRMP2 phosphorylation correlated with decreased CRMP2 binding to Drp1, Miro 2, and KLC1. (S)-LCM rescued CRMP2 binding to Drp1 and Miro 2 but not to KLC1. In parallel with CRMP2 hyperphosphorylation, OA increased mitochondrial fission and suppressed mitochondrial traffic. (S)-LCM prevented OA-induced alterations in mitochondrial morphology and motility. Deletion of CRMP2 with a small interfering RNA (siRNA) resulted in increased mitochondrial fission and diminished mitochondrial traffic. Overall, our data suggest that the CRMP2 expression level and phosphorylation state are involved in regulating mitochondrial morphology and motility in neurons. Full article

(This article belongs to the Special Issue Cell Biology in the United States: Latest Advances and Perspectives)

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18 pages, 1658 KiB

Open AccessArticle

β-Adrenergic Stimulation Synchronizes a Broad Spectrum of Action Potential Firing Rates of Cardiac Pacemaker Cells toward a Higher Population Average

by Mary S. Kim, Oliver Monfredi, Larissa A. Maltseva, Edward G. Lakatta and Victor A. Maltsev

Cells 2021, 10(8), 2124; https://doi.org/10.3390/cells10082124 - 18 Aug 2021

Cited by 8 | Viewed by 2689

Abstract

The heartbeat is initiated by pacemaker cells residing in the sinoatrial node (SAN). SAN cells generate spontaneous action potentials (APs), i.e., normal automaticity. The sympathetic nervous system increases the heart rate commensurate with the cardiac output demand via stimulation of SAN β-adrenergic receptors [...] Read more.

The heartbeat is initiated by pacemaker cells residing in the sinoatrial node (SAN). SAN cells generate spontaneous action potentials (APs), i.e., normal automaticity. The sympathetic nervous system increases the heart rate commensurate with the cardiac output demand via stimulation of SAN β-adrenergic receptors (βAR). While SAN cells reportedly represent a highly heterogeneous cell population, the current dogma is that, in response to βAR stimulation, all cells increase their spontaneous AP firing rate in a similar fashion. The aim of the present study was to investigate the cell-to-cell variability in the responses of a large population of SAN cells. We measured the βAR responses among 166 single SAN cells isolated from 33 guinea pig hearts. In contrast to the current dogma, the SAN cell responses to βAR stimulation substantially varied. In each cell, changes in the AP cycle length were highly correlated (R² = 0.97) with the AP cycle length before βAR stimulation. While, as expected, on average, the cells increased their pacemaker rate, greater responses were observed in cells with slower basal rates, and vice versa: cells with higher basal rates showed smaller responses, no responses, or even decreased their rate. Thus, βAR stimulation synchronized the operation of the SAN cell population toward a higher average rate, rather than uniformly shifting the rate in each cell, creating a new paradigm of βAR-driven fight-or-flight responses among individual pacemaker cells. Full article

(This article belongs to the Special Issue Cell Biology in the United States: Latest Advances and Perspectives)

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13 pages, 3027 KiB

Open AccessFeature PaperArticle

Distinct Gene Expression Profiles in Colonic Organoids from Normotensive and the Spontaneously Hypertensive Rats

by Jing Li, Elaine M. Richards, Eileen M. Handberg, Carl J. Pepine and Mohan K. Raizada

Cells 2021, 10(6), 1523; https://doi.org/10.3390/cells10061523 - 17 Jun 2021

Cited by 4 | Viewed by 2812

Abstract

Hypertension is associated with gut bacterial dysbiosis and gut pathology in animal models and people. Butyrate-producing gut bacteria are decreased in hypertension. RNA-seq analysis of gut colonic organoids prepared from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats was used to [...] Read more.

Hypertension is associated with gut bacterial dysbiosis and gut pathology in animal models and people. Butyrate-producing gut bacteria are decreased in hypertension. RNA-seq analysis of gut colonic organoids prepared from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats was used to test the hypothesis that impaired interactions between the gut microbiome and gut epithelium are involved and that these would be remediated with butyrate supplementation. Gene expressions in immune responses including antigen presentation and antiviral pathways were decreased in the gut epithelium of the SHR in organoids and confirmed in vivo; these deficits were corrected by butyrate supplementation. Deficits in gene expression driving epithelial proliferation and differentiation were also observed in SHR. These findings highlight the importance of aligned interactions of the gut microbiome and gut immune responses to blood pressure homeostasis. Full article

(This article belongs to the Special Issue Cell Biology in the United States: Latest Advances and Perspectives)

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Review

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15 pages, 1833 KiB

Open AccessReview

The H⁺ Transporter SLC4A11: Roles in Metabolism, Oxidative Stress and Mitochondrial Uncoupling

by Joseph A. Bonanno, Raji Shyam, Moonjung Choi and Diego G. Ogando

Cells 2022, 11(2), 197; https://doi.org/10.3390/cells11020197 - 7 Jan 2022

Cited by 13 | Viewed by 3839

Abstract

Solute-linked cotransporter, SLC4A11, a member of the bicarbonate transporter family, is an electrogenic H⁺ transporter activated by NH₃ and alkaline pH. Although SLC4A11 does not transport bicarbonate, it shares many properties with other members of the SLC4 family. SLC4A11 mutations can [...] Read more.

Solute-linked cotransporter, SLC4A11, a member of the bicarbonate transporter family, is an electrogenic H⁺ transporter activated by NH₃ and alkaline pH. Although SLC4A11 does not transport bicarbonate, it shares many properties with other members of the SLC4 family. SLC4A11 mutations can lead to corneal endothelial dystrophy and hearing deficits that are recapitulated in SLC4A11 knock-out mice. SLC4A11, at the inner mitochondrial membrane, facilitates glutamine catabolism and suppresses the production of mitochondrial superoxide by providing ammonia-sensitive H⁺ uncoupling that reduces glutamine-driven mitochondrial membrane potential hyperpolarization. Mitochondrial oxidative stress in SLC4A11 KO also triggers dysfunctional autophagy and lysosomes, as well as ER stress. SLC4A11 expression is induced by oxidative stress through the transcription factor NRF2, the master regulator of antioxidant genes. Outside of the corneal endothelium, SLC4A11’s function has been demonstrated in cochlear fibrocytes, salivary glands, and kidneys, but is largely unexplored overall. Increased SLC4A11 expression is a component of some “glutamine-addicted” cancers, and is possibly linked to cells and tissues that rely on glutamine catabolism. Full article

(This article belongs to the Special Issue Cell Biology in the United States: Latest Advances and Perspectives)

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21 pages, 2733 KiB

Open AccessReview

Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation

by Sreepadaarchana Munjuluri, Dru A. Wilkerson, Gagandeep Sooch, Xingjuan Chen, Fletcher A. White and Alexander G. Obukhov

Cells 2022, 11(1), 18; https://doi.org/10.3390/cells11010018 - 22 Dec 2021

Cited by 35 | Viewed by 11339

Abstract

Capsaicin is a potent agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel and is a common component found in the fruits of the genus Capsicum plants, which have been known to humanity and consumed in food for approximately 7000–9000 years. [...] Read more.

Capsaicin is a potent agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel and is a common component found in the fruits of the genus Capsicum plants, which have been known to humanity and consumed in food for approximately 7000–9000 years. The fruits of Capsicum plants, such as chili pepper, have been long recognized for their high nutritional value. Additionally, capsaicin itself has been proposed to exhibit vasodilatory, antimicrobial, anti-cancer, and antinociceptive properties. However, a growing body of evidence reveals a vasoconstrictory potential of capsaicin acting via the vascular TRPV1 channel and suggests that unnecessary high consumption of capsaicin may cause severe consequences, including vasospasm and myocardial infarction in people with underlying inflammatory conditions. This review focuses on vascular TRPV1 channels that are endogenously expressed in both vascular smooth muscle and endothelial cells and emphasizes the role of inflammation in sensitizing the TRPV1 channel to capsaicin activation. Tilting the balance between the beneficial vasodilatory action of capsaicin and its unwanted vasoconstrictive effects may precipitate adverse outcomes such as vasospasm and myocardial infarction, especially in the presence of proinflammatory mediators. Full article

(This article belongs to the Special Issue Cell Biology in the United States: Latest Advances and Perspectives)

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15 pages, 969 KiB

Open AccessReview

Insights into the Regulation of Ciliary Disassembly

by Maulin M. Patel and Leonidas Tsiokas

Cells 2021, 10(11), 2977; https://doi.org/10.3390/cells10112977 - 1 Nov 2021

Cited by 17 | Viewed by 5729

Abstract

The primary cilium, an antenna-like structure that protrudes out from the cell surface, is present in most cell types. It is a microtubule-based organelle that serves as a mega-signaling center and is important for sensing biochemical and mechanical signals to carry out various [...] Read more.

The primary cilium, an antenna-like structure that protrudes out from the cell surface, is present in most cell types. It is a microtubule-based organelle that serves as a mega-signaling center and is important for sensing biochemical and mechanical signals to carry out various cellular processes such as proliferation, migration, differentiation, and many others. At any given time, cilia length is determined by a dynamic balance of cilia assembly and disassembly processes. Abnormally short or long cilia can cause a plethora of human diseases commonly referred to as ciliopathies, including, but not limited to, skeletal malformations, obesity, autosomal dominant polycystic kidney disease, retinal degeneration, and bardet-biedl syndrome. While the process of cilia assembly is studied extensively, the process of cilia disassembly and its biological role(s) are less well understood. This review discusses current knowledge on ciliary disassembly and how different cellular processes and molecular signals converge to carry out this process. This information will help us understand how the process of ciliary disassembly is regulated, identify the key steps that need further investigation, and possibly design therapeutic targets for a subset of ciliopathies that are causally linked to defective ciliary disassembly. Full article

(This article belongs to the Special Issue Cell Biology in the United States: Latest Advances and Perspectives)

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23 pages, 1814 KiB

Open AccessFeature PaperReview

Distinctive Properties and Powerful Neuromodulation of Na_v1.6 Sodium Channels Regulates Neuronal Excitability

by Agnes Zybura, Andy Hudmon and Theodore R. Cummins

Cells 2021, 10(7), 1595; https://doi.org/10.3390/cells10071595 - 25 Jun 2021

Cited by 19 | Viewed by 8250

Abstract

Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Na_v1.6 is highly enriched at the axon initial segment and nodes, making it [...] Read more.

Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Na_v1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Na_v1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Na_v1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Na_v1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Na_v1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Na_v1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation. Full article

(This article belongs to the Special Issue Cell Biology in the United States: Latest Advances and Perspectives)

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