scholarly journals Mechanisms and Regulation of Cardiac CaV1.2 Trafficking

2021 ◽  
Vol 22 (11) ◽  
pp. 5927
Author(s):  
Maartje Westhoff ◽  
Rose E. Dixon
Keyword(s):  
Acute Stress ◽  
Ryanodine Receptors ◽  
Ventricular Myocardium ◽  
Metabolic Demand ◽  
Channel Trafficking ◽  
Endosomal Recycling ◽  
Current Thinking ◽  
Voltage Dependent ◽  
Cav1.2 Channels ◽  
Cardiac Excitation

During cardiac excitation contraction coupling, the arrival of an action potential at the ventricular myocardium triggers voltage-dependent L-type Ca2+ (CaV1.2) channels in individual myocytes to open briefly. The level of this Ca2+ influx tunes the amplitude of Ca2+-induced Ca2+ release from ryanodine receptors (RyR2) on the junctional sarcoplasmic reticulum and thus the magnitude of the elevation in intracellular Ca2+ concentration and ultimately the downstream contraction. The number and activity of functional CaV1.2 channels at the t-tubule dyads dictates the amplitude of the Ca2+ influx. Trafficking of these channels and their auxiliary subunits to the cell surface is thus tightly controlled and regulated to ensure adequate sarcolemmal expression to sustain this critical process. To that end, recent discoveries have revealed the existence of internal reservoirs of preformed CaV1.2 channels that can be rapidly mobilized to enhance sarcolemmal expression in times of acute stress when hemodynamic and metabolic demand increases. In this review, we provide an overview of the current thinking on CaV1.2 channel trafficking dynamics in the heart. We highlight the numerous points of control including the biosynthetic pathway, the endosomal recycling pathway, ubiquitination, and lysosomal and proteasomal degradation pathways, and discuss the effects of β-adrenergic and angiotensin receptor signaling cascades on this process.

Phosphatidylinositol 3,5-bisphosphate increases intracellular free Ca2+ in arterial smooth muscle cells and elicits vasocontraction

2011 ◽  
Vol 300 (6) ◽  
pp. H2016-H2026 ◽  
Author(s):  
Neerupma Silswal ◽  
Nikhil K. Parelkar ◽  
Michael J. Wacker ◽  
Marco Brotto ◽  
Jon Andresen
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Ryanodine Receptors ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
Arterial Smooth Muscle Cells

Phosphoinositide (3,5)-bisphosphate [PI(3,5)P2] is a newly identified phosphoinositide that modulates intracellular Ca2+ by activating ryanodine receptors (RyRs). Since the contractile state of arterial smooth muscle depends on the concentration of intracellular Ca2+, we hypothesized that by mobilizing sarcoplasmic reticulum (SR) Ca2+ stores PI(3,5)P2 would increase intracellular Ca2+ in arterial smooth muscle cells and cause vasocontraction. Using immunohistochemistry, we found that PI(3,5)P2 was present in the mouse aorta and that exogenously applied PI(3,5)P2 readily entered aortic smooth muscle cells. In isolated aortic smooth muscle cells, exogenous PI(3,5)P2 elevated intracellular Ca2+, and it also contracted aortic rings. Both the rise in intracellular Ca2+ and the contraction caused by PI(3,5)P2 were prevented by antagonizing RyRs, while the majority of the PI(3,5)P2 response was intact after blockade of inositol (1,4,5)-trisphosphate receptors. Depletion of SR Ca2+ stores with thapsigargin or caffeine and/or ryanodine blunted the Ca2+ response and greatly attenuated the contraction elicited by PI(3,5)P2. The removal of extracellular Ca2+ or addition of verapamil to inhibit voltage-dependent Ca2+ channels reduced but did not eliminate the Ca2+ or contractile responses to PI(3,5)P2. We also found that PI(3,5)P2 depolarized aortic smooth muscle cells and that LaCl3 inhibited those aspects of the PI(3,5)P2 response attributable to extracellular Ca2+. Thus, full and sustained aortic contractions to PI(3,5)P2 required the release of SR Ca2+, probably via the activation of RyR, and also extracellular Ca2+ entry via voltage-dependent Ca2+ channels.

scholarly journals Regulation of Maximal Open Probability Is a Separable Function of Cavβ Subunit in L-type Ca2+ Channel, Dependent on NH2 Terminus of α1C (Cav1.2α)

2006 ◽  
Vol 128 (1) ◽  
pp. 15-36 ◽  
Author(s):  
Nataly Kanevsky ◽  
Nathan Dascal
Keyword(s):  
Initial Segment ◽  
Xenopus Oocytes ◽  
Surface Expression ◽  
Amino Acid Residues ◽  
Open Probability ◽  
Separable Function ◽  
Voltage Dependent ◽  
Cav1.2 Channels ◽  
Channel Dependent ◽  
Necessary And Sufficient

β subunits (Cavβ) increase macroscopic currents of voltage-dependent Ca2+ channels (VDCC) by increasing surface expression and modulating their gating, causing a leftward shift in conductance–voltage (G-V) curve and increasing the maximal open probability, Po,max. In L-type Cav1.2 channels, the Cavβ-induced increase in macroscopic current crucially depends on the initial segment of the cytosolic NH2 terminus (NT) of the Cav1.2α (α1C) subunit. This segment, which we term the “NT inhibitory (NTI) module,” potently inhibits long-NT (cardiac) isoform of α1C that features an initial segment of 46 amino acid residues (aa); removal of NTI module greatly increases macroscopic currents. It is not known whether an NTI module exists in the short-NT (smooth muscle/brain type) α1C isoform with a 16-aa initial segment. We addressed this question, and the molecular mechanism of NTI module action, by expressing subunits of Cav1.2 in Xenopus oocytes. NT deletions and chimeras identified aa 1–20 of the long-NT as necessary and sufficient to perform NTI module functions. Coexpression of β2b subunit reproducibly modulated function and surface expression of α1C, despite the presence of measurable amounts of an endogenous Cavβ in Xenopus oocytes. Coexpressed β2b increased surface expression of α1C approximately twofold (as demonstrated by two independent immunohistochemical methods), shifted the G-V curve by ∼14 mV, and increased Po,max 2.8–3.8-fold. Neither the surface expression of the channel without Cavβ nor β2b-induced increase in surface expression or the shift in G-V curve depended on the presence of the NTI module. In contrast, the increase in Po,max was completely absent in the short-NT isoform and in mutants of long-NT α1C lacking the NTI module. We conclude that regulation of Po,max is a discrete, separable function of Cavβ. In Cav1.2, this action of Cavβ depends on NT of α1C and is α1C isoform specific.

Thyroid hormone-induced overexpression of functional ryanodine receptors in the rabbit heart

2000 ◽  
Vol 278 (5) ◽  
pp. H1429-H1438 ◽  
Author(s):  
M. Jiang ◽  
A. Xu ◽  
S. Tokmakejian ◽  
N. Narayanan
Keyword(s):  
Thyroid Hormone ◽  
Cardiac Hypertrophy ◽  
Systolic Function ◽  
Ryanodine Receptors ◽  
Ventricular Myocardium ◽  
Rabbit Heart ◽  
Major Protein ◽  
Release Channel ◽  
Thyroid State ◽  
State Dependent

Modifications in the Ca2+-uptake and -release functions of the sarcoplasmic reticulum (SR) may be a major component of the mechanisms underlying thyroid state-dependent alterations in heart rate, myocardial contractility, and metabolism. We investigated the influence of hyperthyroid state on the expression and functional properties of the ryanodine receptor (RyR), a major protein in the junctional SR (JSR), which mediates Ca2+ release to trigger muscle contraction. Experiments were performed using homogenates and JSR vesicles derived from ventricular myocardium of euthyroid and hyperthyroid rabbits. Hyperthyroidism, with attendant cardiac hypertrophy, was induced by the injection of l-thyroxine (200 μg/kg body wt) daily for 7 days. Western blotting analysis using cardiac RyR-specific antibody revealed a significant increase (>50%) in the relative amount of RyR in the hyperthyroid compared with euthyroid rabbits. Ca2+-dependent, high-affinity [3H]ryanodine binding was also significantly greater (∼40%) in JSR from hyperthyroid rabbits. The Ca2+sensitivity of [3H]ryanodine binding and the dissociation constant for [3H]ryanodine did not differ significantly between euthyroid and hyperthyroid hearts. Measurement of Ca2+-release rates from passively Ca2+-preloaded JSR vesicles and assessment of the effect of RyR-Ca2+-release channel (CRC) blockade on active Ca2+-uptake rates revealed significantly enhanced (>2-fold) CRC activity in the hyperthyroid, compared with euthyroid, JSR. These results demonstrate overexpression of functional RyR in thyroid hormone-induced cardiac hypertrophy. Relative abundance of RyR may be responsible, in part, for the changes in SR Ca2+ release, cytosolic Ca2+ transient, and cardiac systolic function associated with thyroid hormone-induced cardiac hypertrophy.

scholarly journals Toward Understanding the Molecular Role of SNX27/Retromer in Human Health and Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Mintu Chandra ◽  
Amy K. Kendall ◽  
Lauren P. Jackson
Keyword(s):  
Cancer Progression ◽  
Membrane Trafficking ◽  
Endosomal Trafficking ◽  
Channel Trafficking ◽  
Sorting Nexin ◽  
Endosomal Recycling ◽  
Multiple Receptors ◽  
Health And Disease ◽  
Physiological Outcomes

Aberrations in membrane trafficking pathways have profound effects in cellular dynamics of cellular sorting processes and can drive severe physiological outcomes. Sorting nexin 27 (SNX27) is a metazoan-specific sorting nexin protein from the PX-FERM domain family and is required for endosomal recycling of many important transmembrane receptors. Multiple studies have shown SNX27-mediated recycling requires association with retromer, one of the best-known regulators of endosomal trafficking. SNX27/retromer downregulation is strongly linked to Down’s Syndrome (DS) via glutamate receptor dysfunction and to Alzheimer’s Disease (AD) through increased intracellular production of amyloid peptides from amyloid precursor protein (APP) breakdown. SNX27 is further linked to addiction via its role in potassium channel trafficking, and its over-expression is linked to tumorigenesis, cancer progression, and metastasis. Thus, the correct sorting of multiple receptors by SNX27/retromer is vital for normal cellular function to prevent human diseases. The role of SNX27 in regulating cargo recycling from endosomes to the cell surface is firmly established, but how SNX27 assembles with retromer to generate tubulovesicular carriers remains elusive. Whether SNX27/retromer may be a putative therapeutic target to prevent neurodegenerative disease is now an emerging area of study. This review will provide an update on our molecular understanding of endosomal trafficking events mediated by the SNX27/retromer complex on endosomes.

Effects of hindlimb suspension on cytosolic Ca2+ and [3H]ryanodine binding in cardiac myocytes

1999 ◽  
Vol 276 (4) ◽  
pp. H1131-H1136
Author(s):  
Guillaume Halet ◽  
Patricia Viard ◽  
Jean-Luc Morel ◽  
Jean Mironneau ◽  
Chantal Mironneau
Keyword(s):  
Ventricular Myocytes ◽  
Binding Capacity ◽  
Ryanodine Receptors ◽  
Hindlimb Suspension ◽  
Scatchard Analysis ◽  
Channel Activity ◽  
Intrinsic Properties ◽  
Release Channel ◽  
Voltage Dependent ◽  
Cell Capacitance

Effects of a 14-day hindlimb suspension were examined on [3H]ryanodine binding to rat ventricular microsomes and on cytosolic Ca2+ concentration ([Ca2+]i) and voltage-dependent Ca2+channels in isolated ventricular myocytes. In suspended rats, the amplitude of the twitch [Ca2+]itransient was increased without significant modifications of the basal [Ca2+]iand sarcoplasmic reticulum content. Because cell capacitance, L-type Ca2+-current density, and Ca2+-channel gating were not significantly modified after suspension, the increase in [Ca2+]iwas expected to reside in a change in ryanodine receptors. Scatchard analysis of [3H]ryanodine binding revealed that suspension enhanced binding by increasing the affinity of the receptors for [3H]ryanodine without affecting the maximal binding capacity. Both Ca2+-release channel activity and [3H]ryanodine binding are modulated by Ca2+. However, the Ca2+ sensitivity of [3H]ryanodine binding remained unchanged after suspension. Taken together, these results suggest that the increase in twitch [Ca2+]itransients after suspension may result from a change in the intrinsic properties of the ryanodine receptors but not from a change in the expression level of these receptors.

A peripheral governor regulates muscle contraction

2011 ◽  
Vol 36 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Brian R. MacIntosh ◽  
M. Reza S. Shahi
Keyword(s):  
Muscle Contraction ◽  
Muscle Activation ◽  
Human Subjects ◽  
Ryanodine Receptors ◽  
Motor Units ◽  
Voluntary Exercise ◽  
Whole Body ◽  
Peripheral Fatigue ◽  
Metabolic Demand ◽  
Membrane Excitability

Active skeletal muscles are capable of keeping the global [adenosine triphosphate (ATP)] reasonably constant during exercise, whether it is mild exercise, activating a few motor units, or all-out exercise using a substantial mass of muscle. This could only be accomplished if there were regulatory processes in place not only to replenish ATP as quickly as possible, but also to modulate the rate of ATP use when that rate threatens to exceed the rate of ATP replenishment, a situation that could lead to metabolic catastrophe. This paper proposes that there is a regulatory process or “peripheral governor” that can modulate activation of muscle to avoid metabolic catastrophe. A peripheral governor, working at the cellular level, should be able to reduce the cellular rate of ATP hydrolysis associated with muscle contraction by attenuating activation. This would necessarily cause something we call peripheral fatigue (i.e., reduced contractile response to a given stimulation). There is no doubt that peripheral fatigue occurs. It has been demonstrated in isolated muscles, in muscles in situ with no central nervous system input, and in intact human subjects performing voluntary exercise with small muscle groups or doing whole-body exercise. The regulation of muscle activation is achieved in at least 3 ways (decreasing membrane excitability, inhibiting Ca2+release through ryanodine receptors, and decreasing the availability of Ca2+in the sarcoplasmic reticulum), making this a highly redundant control system. The peripheral governor attenuates cellular activation to reduce the metabolic demand, thereby preserving ATP and the integrity of the cell.

scholarly journals Voltage-Dependent Modulation of Cardiac Ryanodine Receptors (RyR2) by Protamine

2009 ◽  
Vol 96 (3) ◽  
pp. 113a
Author(s):  
Paula L. Diaz-Sylvester ◽  
Julio A. Copello
Keyword(s):  
Ryanodine Receptors ◽  
Voltage Dependent

Alkaline pH shifts Ca2+ sparks to Ca2+waves in smooth muscle cells of pressurized cerebral arteries

2002 ◽  
Vol 283 (6) ◽  
pp. H2169-H2176 ◽  
Author(s):  
Thomas J. Heppner ◽  
Adrian D. Bonev ◽  
L. Fernando Santana ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cerebral Arteries ◽  
Ryanodine Receptors ◽  
Muscle Cells ◽  
Alkaline Ph ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
A Minor ◽  
External Ph

The effects of external pH (7.0–8.0) on intracellular Ca2+ signals (Ca2+ sparks and Ca2+ waves) were examined in smooth muscle cells from intact pressurized arteries from rats. Elevating the external pH from 7.4 to 7.5 increased the frequency of local, Ca2+transients, or “Ca2+ sparks,” and, at pH 7.6, significantly increased the frequency of Ca2+ waves. Alkaline pH-induced Ca2+ waves were inhibited by blocking Ca2+ release from ryanodine receptors but were not prevented by inhibitors of voltage-dependent Ca2+ channels, phospholipase C, or inositol 1,4,5-trisphosphate receptors. Activating ryanodine receptors with caffeine (5 mM) at pH 7.4 also induced repetitive Ca2+ waves. Alkalization from pH 7.4 to pH 7.8–8.0 induced a rapid and large vasoconstriction. Approximately 82% of the alkaline pH-induced vasoconstriction was reversed by inhibitors of voltage-dependent Ca2+ channels. The remaining constriction was reversed by inhibition of ryanodine receptors. These findings indicate that alkaline pH-induced Ca2+ waves originate from ryanodine receptors and make a minor, direct contribution to alkaline pH-induced vasoconstriction.

scholarly journals Murine Electrophysiological Models of Cardiac Arrhythmogenesis

2017 ◽  
Vol 97 (1) ◽  
pp. 283-409 ◽  
Author(s):  
Christopher L.-H. Huang
Keyword(s):  
Structural Change ◽  
Surface Membrane ◽  
Experimental Studies ◽  
Cardiac Activity ◽  
Cardiac Pacing ◽  
Ventricular Myocardium ◽  
Cellular Tissue ◽  
Cardiac Arrhythmogenesis ◽  
Voltage Dependent ◽  
Intracellular Ca

Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca2+ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca2+ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias.

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