Voltage-gated Ca2+ Channels: Pharmacology, Modulation and their Role in Human Disease (Handbook of Experimental Pharmacology, 279)

Preface
	1. A Bumpy Road Toward Drug Therapies in Ca2+ Channelopathies
	2. Toward Advanced Technology Medicinal Products Targeting Ca2+-Channels
	3. Ca2+-Channel Modulation: New Discoveries Answer (Very) Old Questions
Contents
Part I: Modulation
CaV1.1 Calcium Channel Signaling Complexes in Excitation-Contraction Coupling: Insights from Channelopathies
	1 Skeletal Muscle Excitation-Contraction (EC) Coupling
	2 Essential Proteins for Skeletal Muscle Excitation-Contraction Coupling
		2.1 The Voltage-Sensor CaV1.1
		2.2 The Calcium Release Channel RyR1
		2.3 The Auxiliary β1a Subunit
		2.4 The Adaptor Protein STAC3
	3 Skeletal Muscle Channelopathies
		3.1 CaV1.1 Channelopathies
			3.1.1 Hypokalemic Periodic Paralysis (HypoPP)
			3.1.2 Normokalemic Periodic Paralysis (NormoPP)
			3.1.3 CaV1.1 Related Myopathies
		3.2 RyR1 Channelopathies
			3.2.1 Central Core Disease (CCD) and Dusty Core Disease (DuCD)
			3.2.2 Other Congenital Myopathies Caused by RyR1 Mutations
		3.3 STAC3 Channelopathies
			3.3.1 Native American Myopathy (NAM)
		3.4 Channelopathies Caused by Several EC Coupling Proteins
			3.4.1 Malignant Hyperthermia (MH) Susceptibility
			3.4.2 Myotonic Dystrophy Type 1 (DM1)
	4 Summary and Perspective
	References
Mechanisms of Vascular CaV1.2 Channel Regulation During Diabetic Hyperglycemia
	1 Introduction
	2 Role of CaV1.2 in Smooth Muscle Cells
	3 Effects of Diabetic Hyperglycemia on Vascular CaV1.2
	4 Mechanisms
	5 Pathophysiological Impact
	6 Conclusions/Future Directions
	References
Sympathetic Nervous System Regulation of Cardiac Calcium Channels
	1 Introduction
	2 Biophysical Signature of Adrenergic Regulation of L-Type Channels
	3 Molecular Mechanisms Underlying L-Type Upregulation
	4 Direct Phosphorylation of α1C and β2B Subunits?
	5 Role of C-Terminal Proteolytic Cleavage of α1C?
	6 Increased Trafficking and Clustering of CaV1.2?
	7 Involvement of an Extrinsic Modulator?
	8 Rad, a Central Element for PKA Regulation of CaV1.2
	9 Rad-Dependent Mechanism Recaptures Key Features of PKA Regulation of CaV1.2?
	10 Relevance of Rad Modulation in Cardiomyocytes
	11 Pathophysiological Implications
	12 Conclusions
	References
Modulation of CaV1.2 Channel Function by Interacting Proteins and Post-Translational Modifications: Implications in Cardiovasc...
	1 Cardiovascular CaV1.2 Channel at a Glance
	2 Galectin-1
		2.1 Galectin-1 Overview
		2.2 Galectin-1-Mediated CaV1.2 Regulation in Hypertension
		2.3 Galectin-1 in Cardiac Diseases
		2.4 Regulatory Signalling of Galectin-1
		2.5 Other Galectins
			2.5.1 Galectin Localization and Functions
			2.5.2 Galectin-3 in Cardiovascular Diseases
	3 Cereblon
	4 CaV1.2, Sialylation, and COVID-19
	5 Concluding Remarks
	References
Part II: Pharmacological Approaches
The Role of Striatal Cav1.3 Calcium Channels in Therapeutics for Parkinson´s Disease
	1 Voltage-Gated Calcium Channels and Channelopathies in the Central Nervous System (CNS)
		1.1 Voltage-Gated Calcium Channels and the Cav1 Subfamily
		1.2 CaV1 Subfamily Channelopathies
	2 Physiologic Functions of Cav1.3 Ca2+ Channels in Basal Ganglia
		2.1 The Basal Ganglia
		2.2 The Striatum, Medium Spiny Neurons, and Cav1.3 Channels
		2.3 Substantia Nigra, Tonically Active Dopamine Neurons, and Cav1.3 Channels
	3 Therapeutic Striatal Cav1.3 Targeting for Motor Complications in PD
		3.1 Levodopa Treatment in PD
		3.2 Motor Complications of Levodopa: An Unmet Clinical Need
		3.3 Striatal Cav1.3 Channels Antagonism for LID: The Initial Promise
		3.4 rAAV-Cav1.3-shRNA: An Optimized Alternative to Pharmacological Cav1.3 Silencing
	4 Therapeutic Nigral Cav1.3 Targeting for Neuroprotection in PD
		4.1 Nigral Cav1.3 Channels Antagonism for Neuroprotection: The Initial Promise
		4.2 The Clinical Experience with Pharmacological Cav1.3 Silencing
	5 Advantages and Disadvantages of Gene Therapy
		5.1 Gene Therapy: Clinical Challenges and Advances
		5.2 Gene Therapy for PD
	6 Conclusion: Cav1.3 Silencing Providing a Trifecta of Therapeutic Benefit in PD
	References
Design and Applications of Genetically-Encoded Voltage-Dependent Calcium Channel Inhibitors
	1 Introduction
	2 HVGCC Blockers as Research Tools and Therapeutics
	3 Gaps in the Landscape of HVGCC Blockers
	4 Characteristics of Some Natural GECCIs
	5 Engineering New Functionalities into Natural GECCIs
	6 De Novo Genetically-Encoded Inhibitors
	7 Applications of Designer GECCIs and Future Directions
	References
Part III: Disease Insight from Channelopathies: Consequences for Pharmacology and Therapeutic Strategies
CACNA1C-Related Channelopathies
	1 Introduction
	2 CaV1.2 in Cellular Physiology
	3 CaV1.2 Regulation
	4 Association with Neuropsychiatric Disorders
	5 Timothy Syndrome
	6 Cardiac-Selective CACNA1C Mutations
	7 Neurological Phenotypes
	8 Beyond Loss of Function/Gain of Function
	9 Functional Channel Hotspots and the Emergence of S6-Opathies
	10 Therapeutic Implications
	References
CACNA1D-Related Channelopathies: From Hypertension to Autism
	1 Introduction
	2 CACNA1D (Cav1.3) Genetic Variants Associated with Human Disease
	3 Prediction of Pathogenicity
	4 Models to Study the Functional Consequences of CACNA1D Variants
	5 Genotype-Phenotype Correlation
	6 Ca2+ Channel Blockers: Hope for a Therapy?
	7 Concluding Remarks
	References
CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options
	1 Introduction
	2 Molecular Genetics of CACNA1A Disorders: Brief Overview
	3 One Side of the Clinical Phenotype: Paroxysmal Features
		3.1 Hemiplegic Migraine
		3.2 Episodic Ataxia
		3.3 Epilepsy
		3.4 Paroxysmal Non-epileptic Events
	4 The Other Side of the Clinical Phenotype: Chronic Neurological Manifestations
		4.1 Cerebellar Ataxia and Further Chronic Motor Signs
		4.2 Developmental Delay, Cognitive and Behavioural Features
		4.3 Imaging Findings
	5 Spinocerebellar Ataxia Type 6: A Polyglutamine CACNA1A Disorder
	6 Treatment Options in CACNA1A Disorders
		6.1 Acetazolamide: A Serendipitous Discovery
		6.2 Aminopyridines in the Treatment of Episodic Ataxia
		6.3 Migraine Prophylaxis in FHM1: Flunarizine, Topiramate and Other Compounds
		6.4 The Treatment of CACNA1A Related Epilepsy: Where Do We Stand?
		6.5 Acute Treatment of EA2 and FHM1 Spells
	7 Conclusion and Future Directions
	References
CaV3.2 (CACNA1H) in Primary Aldosteronism
	1 Introduction
	2 The CaV3.2 Calcium Channel
	3 CaV3.2 Calcium Channels in the Healthy Zona Glomerulosa
	4 CaV3.2 Calcium Channels in Primary Aldosteronism
	5 Pharmacology of CaV3.2 Calcium Channels in Primary Aldosteronism
	6 Summary
	References
CaV3.3 Channelopathies
	1 Introduction
	2 Structure and Modulation of CaV3.3
		2.1 The Gating Brake
		2.2 The Selectivity Filter
		2.3 Domain-Specific Functions
		2.4 The IIIS6 Segment
		2.5 The C-Terminus
		2.6 Splice Variants
	3 CaV3.3 Physiology
		3.1 Expression Patterns
		3.2 Thalamic Network Activity
		3.3 Genetic Mouse Models
		3.4 Further Functions in the Nervous System
	4 CaV3.3 and Brain Disease
		4.1 Schizophrenia
		4.2 Other Psychiatric and Neurological Diseases
		4.3 Neurodevelopmental Disease and Epilepsy
	5 Molecular Patho-Mechanism
	6 CaV3 Pharmacology
	7 Discussion
	References
Pathophysiological Roles of Auxiliary Calcium Channel α2δ Subunits
	1 Introduction
	2 Structural Domains and Processing of α2δ Subunit
		2.1 The Amino and Carboxyl Terminus
		2.2 VWA Domain
		2.3 Cache Domain
		2.4 Molecular Structure of α2δ
		2.5 α2δ Processing
		2.6 Splicing
	3 Physiological Role of α2δ Proteins
		3.1 Channel-Dependent Function
		3.2 Channel Independent Function
	4 α2δ Mutations and Related Diseases
		4.1 Mutations of α2δ at the Protein Level
			4.1.1 α2δ-1
			4.1.2 α2δ-2
			4.1.3 α2δ-3
			4.1.4 α2δ-4
		4.2 Genetic Variations in CACNA2D Genes
			4.2.1 CACNA2D1
			4.2.2 CACNA2D2
			4.2.3 CACNA2D3
			4.2.4 CACNA2D4
	5 α2δs Disease Mechanism
	6 α2δ Proteins as Drug Targets
	7 Summary and Outlook
	References