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Calcium-Dependent Signaling in Cardiac Myocytes

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Cardiovascular Signaling in Health and Disease

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Abstract

Calcium (Ca) is a key regulator of cardiac function. Through interactions with various molecular binding partners, Ca controls both acute processes, such as ion channel gating and myofilament contraction, and long-term events such as transcriptional changes that regulate myocardial development, growth, and death. Cardiac myocyte Ca levels are modulated by complex networks of signaling mechanisms and precise subcellular structural organization that fine-tune the myocyte response to any given stimulus and allow for rhythmic contraction. On the other hand, disrupted Ca handling and Ca signaling abnormalities are well-established mediators of contractile dysfunction and transmembrane potential instabilities leading to arrhythmia. In this chapter, we discuss the most recent advances in understanding the complexities of Ca signaling in health and widespread cardiac disease, namely, heart failure and arrhythmia. We specifically focus on novel emerging aspects of Ca/calmodulin-dependent protein kinase II signaling and on ultrastructural changes that have been associated with these disease contexts. Unraveling these spatial and temporal aspects of Ca signaling is key to understanding the profound mechanistic consequences of Ca dysregulation for cardiac myocyte and organ function and imperative to inform future therapies that might improve disease outcomes.

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Abbreviations

β-AR:

β-Adrenergic receptor

μm:

Micrometer

AA:

Amino acid

AC:

Adenylyl cyclase

AF:

Atrial fibrillation

AP:

Action potential

APD:

Action potential duration

ATP:

Adenosine triphosphate

Bin1:

Amphiphysin II or Bridging Integrator 1

Ca:

Calcium

Ca/CaM:

Calcium-calmodulin

CaM:

Calmodulin

CaMKII:

Calcium/calmodulin-dependent protein kinase II

cAMP:

Cyclic adenosine monophosphate

[Ca]i:

Intracellular calcium concentration

Cav1.2:

L-type calcium channel

Cav3.1-3:

T-type calcium channel

CICR:

Calcium-induced calcium release

CPVT:

Catecholaminergic polymorphic ventricular tachycardia

CRISPR:

Clustered regularly interspaced short palindromic repeats

Cx43:

Connexin-43

DAD:

Delayed afterdepolarization

EAD:

Early afterdepolarization

ECC:

Excitation-contraction coupling

Epac:

Exchange factor directly activated by cAMP

FKBP12.6:

FK506 binding protein 12.6

GLUT:

Glucose transporter

GS:

Stimulatory G protein

HCM:

Hypertrophic cardiomyopathy

HDAC:

Histone deacetylase

HF:

Heart failure

HFpEF:

Heart failure with preserved ejection fraction

HFrEF:

Heart failure with reduced ejection fraction

I/R:

Ischemia/reperfusion

I Ca :

Calcium current

I Ca-L :

L-type calcium current

I Ca-T :

T-type calcium current

I K :

Potassium current

I K1 :

Inward rectifier potassium current

I Na :

Sodium current

I Na,L :

Late sodium current

I Na,T :

Transient sodium current

IP3:

Inositol trisphosphate

IP3R:

Inositol trisphosphate receptor

I ti :

Transient inward current

I to :

Transient outward potassium current

JPH2:

Junctophilin-2

jSR:

Junctional sarcoplasmic reticulum

K:

Potassium

KCa2.2:

Calcium-activated potassium channel

KD:

Dissociation constant

kDa:

Kilodalton

KI:

Knock-in

Kir2.1:

Inward rectifier potassium channel

Kir6.2:

Inward rectifier potassium channel

Kv1.4:

Voltage-gated potassium channel

Kv4.2:

Voltage-gated potassium channel

Kv4.3:

Voltage-gated potassium channel

Kv7.1:

Voltage-gated potassium channel

LTCC:

L-type calcium channel

MEF2:

Myocyte enhancer factor 2

MI:

Myocardial infarction

Na:

Sodium

[Na]i:

Intracellular sodium concentration

NaV:

Voltage-dependent sodium channel

NCX:

Sodium-calcium exchanger

NHE:

Sodium-hydrogen exchanger

NKA:

Sodium/potassium ATPase

nm:

Nanometer

nM:

Nanomolar

NOS:

Nitric oxide synthase

O-GlcNAc:

O-linked β-N-acetylglucosamine

PDE5 :

Phosphodiesterase 5

PKA:

Protein kinase A

PLB:

Phospholamban

PTM:

Posttranslational modification

ROS:

Reactive oxygen species

RyR:

Ryanodine receptor

SCN5A:

Sodium voltage-gated channel alpha subunit 5

SERCA:

Sarco/endoplasmic reticulum calcium ATPase

SGLT:

Sodium-glucose cotransporter

SK2:

Small-conductance Calcium-activated potassium channel

SR:

Sarcoplasmic reticulum

TA:

Triggered action potential

TT:

Transverse (t)-tubule

TTCC:

T-type calcium channel

WT:

Wild-type

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  1. Christopher Y. Ko and Charlotte E. R. Smith contributed equally.

Authors and Affiliations

  1. Department of Pharmacology, University of California at Davis, Davis, CA, USA

    Christopher Y. Ko, Charlotte E. R. Smith & Eleonora Grandi

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  1. Christopher Y. Ko
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  2. Charlotte E. R. Smith
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Correspondence to Charlotte E. R. Smith .

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  1. Division of Pulmonary, Critical Care, and Sleep Medicine Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Narasimham L. Parinandi

  2. Departments of Biomedical Engineering and Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA

    Thomas J. Hund

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Ko, C.Y., Smith, C.E.R., Grandi, E. (2022). Calcium-Dependent Signaling in Cardiac Myocytes. In: Parinandi, N.L., Hund, T.J. (eds) Cardiovascular Signaling in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-031-08309-9_1

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