Note: Intro -- Preface -- Contents -- Part I: Cyclic Nucleotide Microdomains -- 1: Receptor-Cyclic Nucleotide Microdomains in the Heart -- 1.1 Introduction -- 1.2 Biosensors for cAMP and cGMP -- 1.3 Mechanisms of Compartmentation in Microdomains -- 1.4 Receptor-cAMP/cGMP Microdomain Visualization -- References -- 2: Membrane Microdomains and cAMP Compartmentation in Cardiac Myocytes -- 2.1 Introduction -- 2.2 Membrane Microdomains -- 2.3 Receptor-Mediated Responses -- 2.3.1 β1-Adrenergic Receptors (β1ARs) -- 2.3.2 β2-Adrenergic Receptors (β2ARs) -- 2.3.3 M2 Muscarinic Receptors (M2Rs) -- 2.3.4 Prostaglandin Receptors (EPRs) -- 2.4 Conclusions and Future Directions -- References -- 3: Function to Failure: Compartmentalization of Cardiomyocyte Signaling by A-Kinase-Anchoring Proteins -- 3.1 Introduction -- 3.2 AKAPs and Regulation of the Calcium Cycle -- 3.2.1 AKAP7 (Small Isoforms) -- 3.2.2 AKAP7 (Large) -- 3.2.3 AKAP5 (AKAP75/AKAP79/AKAP150) -- 3.3 AKAPs and Cardiac Remodeling -- 3.3.1 AKAP6 -- 3.3.2 AKAP13 -- 3.4 Other AKAPs with Characterized Functions -- References -- 4: Pharmacological Approaches for Delineating Functions of AKAP-Based Signalling Complexes and Finding Therapeutic Targets -- 4.1 Introduction -- 4.1.1 The cAMP Signalling Cascade -- 4.1.2 cAMP Effectors -- 4.1.3 cAMP Signalling Compartments -- 4.2 A-Kinase Anchoring Proteins (AKAPs) -- 4.2.1 AKAP-PKA Interactions -- 4.2.2 The Role of AKAPs in the Heart and Cardiovascular Diseases Exemplifies Their Potential Value as Drug Targets -- 4.3 AKAP-PKA Disruptors -- 4.3.1 Peptides -- 4.3.1.1 Binding to R-Subunits of PKA -- 4.3.1.2 Binding to AKB Domains of AKAPs -- 4.3.1.3 Modified Peptides -- 4.3.2 Peptidomimetics -- 4.3.3 Small Molecules -- 4.3.4 Disruptors of Interaction Between AKAPs and Proteins Other Than PKA -- 4.4 Conclusions and Outlook. , References -- 5: Chatting Second Messengers: PIP3 and cAMP -- 5.1 Introduction -- 5.2 PIP3: A Signaling Lipid on Membranes -- 5.3 Mechanisms of Cross-Talk between PIP3 and cAMP Signaling -- 5.3.1 PIP3-Mediated Downregulation of β-AR/cAMP Signaling in Heart Failure -- 5.3.2 PIP3- and PI3K-Dependent Control of cAMP Hydrolysis -- 5.3.3 cAMP-Mediated Regulation of PIP3 Signaling -- References -- 6: Cyclic Nucleotide Phosphodiesterases and Compartmentation in Normal and Diseased Heart -- 6.1 Introduction -- 6.2 CN Signalling in Cardiac Myocytes -- 6.3 Overview of the PDE Superfamily -- 6.4 Role of PDEs in Cyclic Nucleotide Compartmentation -- 6.5 PDEs and Cyclic Nucleotide Compartmentation in Heart Failure -- 6.6 PDEs as Therapeutic Targets in Ischemia/Reperfusion Injury? -- 6.7 Concluding Remarks -- References -- 7: cAMP Compartmentalisation and Hypertrophy of the Heart: 'Good' Pools of cAMP and 'Bad' Pools of cAMP Coexist in the Same Cardiac Myocyte -- 7.1 cAMP Signalling in the Heart -- 7.2 Compartmentalisation of the cAMP Signalling Pathway -- 7.3 Compartmentalisation of GPCRs and ACs -- 7.4 PKA Compartmentalisation via AKAPs -- 7.5 PDEs and cAMP Compartmentalisation -- 7.6 cAMP/PKA Signalling in Cardiac Hypertrophy: Opposing Effects of Spatially Distinct Pools of cAMP -- References -- 8: Subcellular Targeting of PDE4 in Cardiac Myocytes and Generation of Signaling Compartments -- 8.1 Introduction -- 8.2 A Brief Description of the PDE4 Family of Enzymes -- 8.3 PDE4 Expressed in Cardiac Myocytes: Comparison of Different Species -- 8.4 Subcellular Localization of PDE4s -- 8.5 Molecular Basis of PDE4 Targeting to Different Subcellular Structures in Cardiac Myocytes -- 8.6 PDE4 Control of Distinct Pools of cAMP in Cardiac Myocytes and Different Ca2+ Handling Components -- References. , 9: Cardiac cAMP Microdomains and Their Modulation Using Disruptor Peptides -- 9.1 Introduction -- 9.2 PDE4 Localization -- 9.3 The Arrestin-PDE4D5 Complex -- 9.4 The HSP20-PDE4D Complex -- 9.5 Disruptors of AKAP-PKA in the Heart -- 9.6 EPAC Disruptors -- 9.7 Conclusions and Future Directions -- References -- 10: Computational Modeling of Cyclic Nucleotide Signaling Mechanisms in Cardiac Myocytes -- 10.1 Introduction -- 10.1.1 Overview of the cN Signaling System -- 10.1.2 cN Signaling Pathways and Cardiac Function -- 10.1.3 Overview of Mechanistic Models of cN Signaling Pathways -- 10.2 Modeling Multiple PDE Interactions in Cardiac Myocytes -- 10.2.1 Diverse PDE Families in Cardiac Myocytes -- 10.2.2 Mechanistic Models of PDEs -- 10.2.3 Cross-Talk between cN Signaling Pathways -- 10.3 Modeling Regulation of Cardiac Electrophysiology by the cN Signaling System -- 10.3.1 Overview of Models of Cardiac EC Coupling -- 10.3.2 PKA-Mediated Phosphorylation of EC Coupling Proteins -- 10.3.3 PKG-Mediated Phosphorylation of EC Coupling Proteins -- 10.3.4 Effects of Dual Phosphorylation by PKA and PKG -- 10.4 Modeling Spatially Resolved cN Signaling in Cardiac Myocytes -- 10.4.1 Compartmentation of cN Signaling -- 10.4.2 PDE Localization as a Mechanism Underlying cN Compartmentation -- 10.5 Modeling cN Signaling System in Heart Failure -- 10.5.1 Changes in cN Synthesis in the Failing Heart -- 10.5.2 Changes in Expressions and Activities of PDEs in the Failing Heart -- 10.5.3 Changes in Spatial Localization of cN Signaling in the Failing Heart -- 10.5.4 Changes in Phosphorylation Status of EC Coupling Proteins in the Failing Heart -- 10.6 Multi-Type Data Integration and Fusion via Modeling -- References -- 11: Signalling Microdomains: The Beta-3 Adrenergic Receptor/NOS Signalosome -- 11.1 Introduction. , 11.2 Identification of a Gαi-NOS Signalling Pathway Downstream of Cardiac β3AR Activation -- 11.3 Signalling Elements in the NO/cGMP Pathway -- 11.3.1 Nitric Oxide Synthases -- 11.3.2 Soluble Guanylate Cyclase -- 11.3.3 Cardiac cGMP Effectors -- 11.3.3.1 Cardiac cGKI -- 11.3.3.2 Cardiac PDEs: cGMP Catabolism and Compartmentalisation -- cGMP-hydrolysing PDEs -- Compartmentalisation of cGMP Signals and Crosstalk Between cGMP and cAMP Signals -- 11.4 NOS-sGC-cGMP Signalling Pathways and Cardiac Remodelling -- 11.4.1 Cardiac NOS Isoforms and Cardiac Remodelling -- 11.4.2 sGC and Cardiac Remodelling -- 11.4.3 PDE5 Inhibition and Cardiac Remodelling -- 11.4.4 β3ARs and Cardiac Remodelling -- 11.4.5 Mechanisms of cGMP Modulation of Cardiac Remodelling -- 11.4.6 cGMP-cGK-Dependent Modulation of Pathological Ca2+ Signals -- 11.4.6.1 Other Mechanisms of cGMP-cGKI Modulation of Pathological Remodelling -- References -- 12: Compartmentation of Natriuretic Peptide Signalling in Cardiac Myocytes: Effects on Cardiac Contractility and Hypertrophy -- 12.1 Introduction -- 12.2 Natriuretic Peptides and Their Receptors in Cardiomyocytes -- 12.3 Compartmentation of Natriuretic Peptide-Induced Effects -- 12.3.1 Signalling of Natriuretic Peptides Causing Contractile Effects -- 12.3.2 Signalling of Natriuretic Peptides Causing Antihypertrophic Effects -- 12.3.3 Crosstalk Between Natriuretic Peptide-Induced cGMP and cAMP -- 12.3.4 Regulation of cGMP Levels and cGMP-Dependent Effects by PDEs -- 12.3.5 cGMP-Independent Signalling of Natriuretic Peptides -- 12.4 Consequences of Compartmentation of Natriuretic Peptide Signalling -- 12.4.1 What Determines if Natriuretic Peptides Cause Negative or Positive Inotropic Responses? -- 12.4.2 Natriuretic Peptide Signalling-Beneficial or Not?. , 12.4.3 Compartmentation of the cGMP Signal Generated by NPR-A and NPR-B -- 12.5 Visualising cGMP After NPR Stimulation in Cardiomyocytes -- References -- 13: Cyclic GMP/Protein Kinase Localized Signaling and Disease Implications -- 13.1 Introduction -- 13.2 Modulation of cGMP by NO or NP Pathways -- 13.3 Modulation of cGMP/PKG by Localized PDEs in the Heart -- 13.4 Modifying Intracellular Localization and Targeting by cGMP/PKG -- 13.5 Role of Oxidative Stress in Altering cGMP/PKG Signaling -- References -- Part II: Calcium Microdomains -- 14: Distribution and Regulation of L-Type Ca2+ Channels in Cardiomyocyte Microdomains -- 14.1 Introduction -- 14.2 Microdomain-Specific Distribution and Regulation of LTCCs in Ventricular Myocytes -- 14.2.1 T-Tubule (Dyads) -- 14.2.2 Lipid Rafts/Caveolae -- 14.2.3 Nucleus -- 14.2.4 ß-Adrenergic Regulation of the LTCC Subpopulation in Caveolar Microdomains -- 14.2.5 Heart Failure-Associated Remodeling of Cardiomyocyte Microdomains and LTCCs -- 14.2.5.1 T-Tubular/Dyadic Microdomains in Cardiovascular Disease and Consequences for LTCCs -- 14.2.5.2 Caveolar Microdomains in Cardiovascular Disease and Consequences for LTCCs -- 14.2.5.3 ß-Adrenergic Microdomains in Cardiovascular Disease and Consequences for LTCCs -- 14.3 Microdomain-Specific Distribution and Regulation of LTCCs in Atrial Myocytes -- 14.3.1 T-Tubule Structure in Atrial versus Ventricular Myocytes -- 14.3.2 Microdomain-Specific Distribution and Biophysics of Atrial LTCC -- 14.3.3 LTCCs and Unique Atrial Ca2+ Signaling -- 14.3.4 LTCC Remodeling in HF and Atrial Fibrillation -- 14.3.4.1 Atrial Fibrillation -- 14.3.4.2 Heart Failure -- References -- 15: The Role of Local Ca2+ Release for Ca2+ Alternans and SR-Ca2+ Leak -- 15.1 Introduction -- 15.2 Ca2+ Microdomains in Cardiac Myocytes -- 15.2.1 Subsarcolemmal Space -- 15.2.2 Dyadic Cleft. , 15.2.3 Mitochondria.

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