Voltage-Gated Calcium Channels

Preface
Contents
A Lived History of Early Calcium Channel Discoveries Over the Past Half-Century
Ca2+ as Central Ion for Muscle Contraction
The “Ca-Spikes” of Crustacean Skeletal Muscles
“Ca-Spikes” in Heart and Neurons
How to Look at Ca2+ Currents Through Voltage-Clamp Recordings
Ca2+ Currents in the Heart and Mollusc Neurons: The Problem of Blocking K+ Currents
A Convergent View on the Existence of “a” Ca2+ Channel in Excitable Cells
The “Patch-Clamp” Technique and the Explosive Interest on Ca2+ Channels
The Discovery of the “Low-Voltage Activated” T-Type Channel
The Unique Properties of T-Type (LVA) Channels
The Explosive Interest on T-Type Channels
The Ca2+ Channel Family Growths
The N-Type Channel
The P/Q-Type Channel
The R-Type Channel
From Ionic Currents to the Molecular Structure of Ca2+ Channels
The cAMP-Mediated Enhancement of Cardiac L-Type Channels as First Example of Ca2+ Channel Modulation
Early Observations on the GPCR-Mediated Inhibition of Neuronal Ca2+ Channels
Towards a Full Understanding of the GPCR-Induced Delayed Activation of HVA Channels
Looking Deeper to the Structure and Function of Cav2 Channels Modulation by G proteins
Take-Home Message
References
Part I: Structural and Molecular Aspects of VGCCs
Subunit Architecture and Atomic Structure of Voltage-Gated Ca2+ Channels
Introduction
Purification and Biochemical Characterization of Skeletal Muscle Calcium Channels
Structures of NaVAb and CaVAb Channels
Structure of the Skeletal Muscle CaV1.1 Calcium Channel
Molecular Properties of the CaV2 Family of Calcium Channels
Structure of CaV2.2 Calcium Channels and Implications for Regulation
Molecular Properties and Structure of CaV3 Calcium Channels
Pharmacology of Calcium Channels
Conclusion
References
Splicing and Editing to Fine-Tune Activity of High Voltage-Activated Calcium Channels
Generation of mRNA Diversity by A-to-I RNA Editing and Alternative Splicing
Splice Variations in High Voltage-Activated Calcium Channels
CaV1.1 Splice Variant in Myotonic Dystrophy
CaV1.2 Splice Variants in Health and Disease
Exon 9* in Cardiovascular Diseases
Mutually Exclusive Exons 1a/1 and Exons 8a/8
Exons 21/22
Exon 33 and Exon 33L
CaV1.3 in Health and Disease
The Pathophysiological Roles of CaV1.3
The Unique Biophysical and Pharmacological Properties of CaV1.3 Channels and Modulation
Regulation of α1D Transcripts by Alternative Splicing and A-to-I RNA Editing
CaV1.4 in Health and Disease
Structure–Function Relationship Learnt from Human Mutations and Alternative Splicing Patterns
The CaV2 Channel Family
Pathophysiological Roles of CaV2 Channel Family
Alternative Splicing in CaV2 Channel Family
Exon 37
Exon 43/44
Exon 47
Novel Approaches to Uncover the Pathophysiological Consequences of Alternative Splicing or Gene Mutations of Ion Channels: Moving Away from Heterologous Systems
Summary
References
Voltage-Gated Calcium Channel Auxiliary β Subunits
Physiological Roles of High-Voltage-Activated Calcium Channels
Subunits of Voltage-Gated Calcium Channels
Physiological Roles of CaVβ Subunits
Functional Effects of CaVβ Subunits in HVACC Complexes
CaVβ Regulation of HVACC Membrane Trafficking
CaVβ Regulation of HVACC Activation Gating
CaVβ Regulation of HVACC Open Probability
CaVβ Regulation of HVACC Inactivation Gating
Structure–Function of CaVβ Regulation of HVACCs
CaVβ-Interacting Proteins That Regulate HVACCs
Regulation of HVACCs by RGK Proteins
Roles of CaVβ and Rad in Sympathetic Regulation of Cardiac CaV1.2
RIM-Binding Protein Regulation of HVACCs
Association of CaVβ Subunits with Disease
Pharmacological Targeting of CaVβ Subunits
References
Regulation of Calcium Channels and Synaptic Function by Auxiliary α2δ Subunits
Introduction
Discovery of α2δ Subunits
Identification of α2δ Subunits
Cloning
Splice Variants
Tissue Distribution of α2δ Subunits
α2δ-1
α2δ-2
α2δ-3
α2δ-4
Structure of α2δ Subunits
Biochemical and Bioinformatic Studies
GPI Anchoring
VWA Domain
Cache Domains
Proteolytic Maturation of α2δ
Cachd1 Protein
Molecular Structure of α2δ-1
Functions of α2δ Subunits as Calcium Channel Subunits
Effects of Cloned α2δ Subunits on Calcium Currents
Effects of α2δ Subunits on Biophysical Properties of Calcium Currents
Effects of α2δ Subunits on Calcium Channel Trafficking
Cachd1 Function
Synaptic Functions of α2δ Proteins Beyond Their Role as Calcium Channel Subunits
Importance of α2δ Proteins in Neuronal and Synaptic Functions
Postsynaptic Functions of α2δ-1
Presynaptic and Trans-synaptic Roles of α2δ Proteins
Diseases Associated with α2δ Subunits
Ducky Mice and Human Mutations of the α2δ-2 Gene
Mutations in the α2δ-1 Gene Associated with Cardiac Phenotypes
Neuropathic Injury and the Role of α2δ-1
Disorders Associated with α2δ-3
Disorders Associated with α2δ-4
Psychiatric Disorders
Pharmacology Involving α2δ Subunits
Therapeutic Uses of Gabapentinoids
Gabapentinoid Drug Binding to α2δ Subunits and Potential Mechanisms of Action
The First Double Cache Domain in α2δ-1 Has Structural Homology to a Universal Amino Acid Binding Domain
Effect of α2δ Subunits on Ziconotide Binding
Other Interactions of α2δ Proteins
Summary and Outlook
References
Voltage-Gated Calcium Channels in Invertebrates
Introduction: Invertebrates and Calcium Channel Discovery
Phylogenetic Properties of the CaV Channel α1 Subunit
Phylogenetic Properties of the CaV Channel β Subunit
Phylogenetic Properties of the CaV Channel α2δ Subunit
CaV Channels in Deuterostome Invertebrates
Since Hagiwara’s Discovery of LVA and HVA Ca2+ Currents in Starfish Eggs
Tunicates and the Evolution of CaV1.1 Channels and Ryanodine Receptor Tetrad Coupling
CaV Channels in Protostome Invertebrates
The Atypical Nature of Calcium Channels in Parasitic Flatworms
Functional Studies of Calcium Channels of the Pond Snail Lymnaea Stagnalis
Genetic Studies of Ecdysozoan β and α2δ Subunits Highlight Gene Duplication as a Mechanism for Functional Diversification and the Emergence of Pleiotropic Functions
Genetic and Functional Studies of Ecdysozoan CaV1–CaV3 Channels Reveal Deep Conservation of C-Terminal Protein Interactions and Sub-cellular Localization
CaV Channels in Early-Diverging Animals
Cnidaria: Our Most Distant Neural Ancestors?
Evolutionary Insights from Functional Studies of the Placozoan CaV1 to CaV3 Channels
A Calcium Channel Regulates Choanocyte Ciliary Beating and the Feeding Current in Sponges
Ctenophores
Conclusions
References
Untitled
Part II: Regulation of VGCCs
Modulation of VGCCs by G-Protein Coupled Receptors and Their Second Messengers
Introduction
Modulation of Cav1 Channels by GPCRs and Second Messengers
β-Adrenergic Modulation of L-Type Channels: Activation of the Gs Signaling Pathway
Gq-Coupled GPCR Modulation of L-Type Channels
Gi/o-Coupled GPCR Modulation of L-Type Channels
GPCR-Mediated Modulation of Cav1.4 in the Retina
Modulation of Cav2 Channels by GPCRs and Second Messengers
Mechanisms Gi/o Mediated Inhibition: Fast, Direct, Voltage-Dependent
Cav2 Channel Interaction Sites with Gβγ Subunits
Gβγ and Cavβ Subunit Diversity and Interaction Sites with Cav2 Channels
Modulation of G Protein-Mediated Inhibition by Synaptic Associated and Other Proteins
Regulation of Cav2 Channels by Lipids
Mechanisms of Gq/11-Mediated Inhibition: Slow, Indirect, Voltage-Independent
Conclusion for Cav2 Channels
Modulation of Cav3 Channels by GPCRs and Second Messengers
Direct Modulation by Gβγ Subunits
Modulation by Kinases
Protein Kinase A
Protein Kinase C
Calmodulin-Dependent Kinase II
Protein Kinase G
Rho-Kinase
Tyrosine Kinase
GPCR-Mediated Change in T-Type Channel Expression
Conclusion for T-Type Channels
Summary
References
Trafficking of Neuronal Calcium Channels
Introduction
Regulation of VGCCs by Ancillary Subunits
Cavβ-Subunit
Cavα2δ-Subunit
Cavγ-Subunit
Regulation of VGCCs by Other Interacting Proteins
Calmodulin
Collapsin Response Mediator Proteins
Stac Adaptor Proteins
Kelch-like 1
Calnexin
Secretory Carrier-Associated Membrane Proteins
Receptor for Activated C kinase 1
Regulation of VGCCs by Posttranslational Modifications
Ubiquitination
Glycosylation
Subcellular Targeting of VGCCs
Concluding Remarks and Perspectives
References
Calmodulin Regulation of Voltage-Gated Calcium Channels
Introduction
Ca2+/CaM-Dependent Regulation of VGCCs
Ca2+/CaM-Dependent Regulation Responds Differentially to Spatially Distinct Ca2+ Sources
Molecular Mechanism of Calmodulation
Ca2+ Regulation of VGCCs in Disease
References
Cav3 Calcium Channel Interactions with Potassium Channels
Introduction
Cav3-Kv4 Complex
Cav3.2-IK Complex
Cav3.2-BK Complex
Perspectives and Conclusions
References
Part III: (Patho)physiology of VGCCs
Voltage-Gated Ca2+ Channels. Lessons from Knockout and Knock-in Mice
Introduction
CaV1
CaV1.1
Muscle Contraction and Development: Cacna1s−/− (Dysgenic) Mice
CaV1.1 Ca2+ Conductance and Skeletal Muscle Function: Cacna1sN617D, Cacna1sE1014K Knock-In (KI) Mice
Neuromuscular Junction Development: Cacna1sN617D, RyR1−/−/Cacna1sN617D, Cacna1sΔE29, Cacna1sΔE29/RyR1−/− Mutant Mice
Developmentally Regulated Alternative Splicing in Muscle Function: Cacna1sΔE29 Mutant Mice
CaV1.1 in Human Disease: Cacna1sR528H KI Mice
CaV1.2 and CaV1.3
CaV1.2
Cav1.2 in the Heart: Conventional and Conditional Cacna1c KO
Dissecting CaV1.2 and CaV1.3 Channel Function: Cav1.2DHP−/− (Cacna1cT1066Y) KI Mice
CaV1.2 in Smooth Muscle: Conditional Cacna1c KO and CaV1.2DHP−/− KI Mice
Endocrine Pancreas: Conditional Cacna1c KO and CaV1.2DHP−/− KI Mice
CaV1.2 in Timothy Syndrome: Cacna1cG406R KI (TS2-NEO) and Cacna1cG406R-Expressing Transgenic Mice
Molecular Mechanisms Fine-Tuning CaV1.2 Activity: Cacna1c KI, Exon Deletion and Transgenic Mice
Auditory Function: Conditional KI Mice
Brain Function of CaV1.2: Conditional KO and KI Mice
L-type Channels in Glial Function, Myelination and Remyelination: Conditional Cacna1c KO and Conditional Transgenic CaV1.2 α1 shRNA Expression
CaV1.3
Cardiac Excitability and Inotropy: Constitutive KO and CaV1.2DHP−/− Mice
Cochlear Inner Hair Cell Function and Hearing: Constitutive and Conditional KO
Intestinal Ca2+ Absorption and Bone Development: Constitutive KO
Endocrine Function: Constitutive KO and CaV1.2DHP−/− KI
Pharmacological Separation of CaV1.2 from CaV1.3 Functions: Cav1.2DHP−/− KI Mice
Modulatory Role of the CaV1.3 α1 CTM Domain: Cacna1d DCRDHA KI Mice
CaV1.3 Channels in Spinal Cord Injury: Constitutive/Conditional Cacna1d KO Mice
Other Functions of CaV1.3: Constitutive KO Mice
CaV1.2 and CaV1.3
Neuron and Brain Function of CaV1.2 and CaV1.3 Channels: Conditional Cacna1c KO Mice, Cacna1d−/−, and CaV1.2DHP−/− Mice
Cognitive Function in a Mouse Model for an “Aged” Brain: Transgenic Overexpression of CaV1.3 α1 in the Brain
L-Type Channels in Fear Responses: Constitutive/Conditional CaV1.2 and Constitutive Cacna1d KO
L-Type Channels in Drug Taking Behaviors: Conditional Cacna1c KO, Constitutive Cacna1c KO and CaV1.2DHP−/− Mice
L-Type Channels in Brain Dopamine Neurons: Constitutive Cacna1d KO and CaV1.2DHP−/− Mice
L-Type Channels in the Immune System: Conditional Cacna1c KO, Constitutive CaV1.3 and CaV1.4 KO
Rat Model of CaV1.2 Haploinsufficiency
CaV1.4
CaV2
CaV2.1
Early Reports of CaV2.1 Mutant Mice
Neuronal Processes and Deficits: Conventional CaV2.1 KO
Neuronal Processes and Deficits: Conditional CaV2.1 KO
Extended Knowledge of CaV2.1 Mutant Mice
Exocytosis and Neurotransmitter Release: Conventional CaV2.1 KO
Presynaptic Protein Interaction: Conditional CaV2.1 KO
Biochemical Characterization of the Two-Domain 95kD Short Form: Conventional CaV2.1 KO
Cerebellar Function and Maturation: Conventional/Conditional CaV2.1 KO
Synaptic Plasticity at the Neuromuscular Junction and in the Hippocampus: CaV2.1 KI
Cognition and Neuronal Electrical Oscillations: Conventional/Conditional CaV2.1 KO
Epilepsy: Conditional CaV2.1 KO
Mouse Models for Neurological Diseases: CaV2.1 KI
Pain: Conventional CaV2.1 KO
CaV2.2
Early Reports of CaV2.2 Mutant Mice
Sympathetic Regulation: Conventional CaV2.2 KO
Pain: Conventional CaV2.2 KO
Extended Knowledge of CaV2.2 Mutant Mice
Pharmacological Effects: Conventional CaV2.2 KO
Neurotransmitter Release: Conventional CaV2.2 KO
Sympathetic Regulation: Conventional CaV2.2 KO
Behavior, Memory, and Cognition: Conventional CaV2.2 KO
Endothelium-Dependent Relaxation and Autonomic Regulation of Cardiovascular Function: Conventional CaV2.2 KO
Diabetic Kidney Dysfunction: Conventional CaV2.2 KO
CaV2.3
Early Reports of CaV2.3 Mutant Mice
R-Type Identification: Conventional and Conditional CaV2.3 KO
Pain: Conventional CaV2.3 KO
Amygdala Function: Conventional CaV2.3 KO
Extended Knowledge of CaV2.3 Mutant Mice
Pain: Conventional CaV2.3 KO
Pancreatic Function and Glucose Metabolism: Conventional CaV2.3 KO
Distribution in the Brain: Conventional CaV2.3 KO
Synaptic Plasticity in the Hippocampus and Cerebellum: Conventional CaV2.3 KO
Sleep: Conventional CaV2.3 KO
T-Type in Sperm: Conventional CaV2.3 KO
Seizure and Epilepsy: Conventional CaV2.3 KO
Epilepsy: Conventional CaV2.3 KO
Ischemic Neuronal Injury: Conventional CaV2.3 KO
Narcotic Effects: Conventional CaV2.3 KO
Anesthesia: Conventional CaV2.3 KO
Parkinson Disease: Conventional CaV2.3 KO
Cardiac Arrhythmia and Altered Autonomic Control: Conventional CaV2.3 KO
CaV3
CaV3.1
Early Reports of CaV3.1 Mutant Mice
Epilepsy: Conventional CaV3.1 KO
Anesthesia: Conventional CaV3.1 KO
Sleep: Conditional CaV3.1 KO
Extended Knowledge of CaV3.1 Mutant Mice
Cardiac Pacemaker Activity and Vascular Dilation: Conventional CaV3.1 KO
Cerebellar Functions: Conventional CaV3.1 KO
Behavior and Hippocampal Oscillation: Conventional CaV3.1 KO
Sleep: Conventional CaV3.1 KO
Epilepsy: Conventional CaV3.1 KO and CaV3.1 Transgenic Overexpression
Pain: Conventional CaV3.1 KO
Anesthesia: Conventional CaV3.1 KO
Mouse Model for Spinocerebellar Ataxia: CaV3.1 KI
Sperm: Conventional CaV3.1 KO
Immune System: Conventional and conditional CaV3.1 KO
CaV3.2
CaV3.2 in Arterial Vascular Tone: Conventional CaV3.2 KO (Cacna1h−/−)
CaV3.2 vs. CaV3.1 in Arterial Vascular Tone: Conventional Cacna1g and Cacna1h KO
CaV3.2 in the Heart: Conventional CaV3.2 KO (Cacna1h−/−) and Cacna1h−/−/NFAT-Luc Double Transgenic Mice
CaV3.2 vs. CaV3.1 in the Heart: Conventional Cacna1g and Cacna1h KO, Cacna1g-Overexpressing Mice (Cardiomyocyte-Specific)
CaV3.2 and Hearing Function: Conventional Cacna1h KO
Sensory Systems: Conventional/Conditional CaV3.2 KO and CaV3.2 KI
Pain: Conventional/Conditional CaV3.2 KO and CaV3.2 KI
Analgesia and Anesthesia: Conventional CaV3.2 KO
Itch: Conventional CaV3.2 KO
Epilepsy: Conventional CaV3.2 KO
Memory: Conventional CaV3.2 KO
Neuronal Excitability: Conventional CaV3.2 KO
Expression Distribution in the Brain: Conventional CaV3.2 KO
Neuroprotection: Conventional CaV3.2 KO
Neurogenesis: Conventional CaV3.2 KO
Retina: Conventional CaV3.2 KO
Carotid Body and Hypoxia Sensing: Conventional CaV3.2 KO
Gastrointestinal Tract: Conventional CaV3.2 KO
Hypertension: Conventional CaV3.2 KO and M1560V KI
Fertilization: Conventional CaV3.2 KO
Bone: Conventional CaV3.2 KO
CaV3.3
Early Reports of CaV3.3 Mutant Mice
Sleep: Conventional CaV3.3 KO
Epilepsy: Conventional CaV3.3 KO
Extended Knowledge of CaV3.3 Mutant Mice
Sleep: CaV3.3 KO and KI
Anesthesia: Conventional CaV3.3 KO
Multiple CaVs
Presynapse: Conventional KO for CaV2.1, CaV2.2, or CaV2.3
Presynapse: Conditional Triple CaV2 KO
Sleep: Conventional Double CaV3.2/CaV3.3 KO
Sleep: Conventional KO for CaV1.1~1.4, CaV2.1~2.3, or CaV3.1~3.3
Epilepsy: Conventional Double CaV2.1/CaV3.1 KO
Epilepsy: Conditional CaV2.1 KO with Conventional CaV3.1 or CaV3.2 KO
Epilepsy: Conventional CaV3.1 or CaV3.2 KO
Sympathetic Activity: Conventional KO for CaV3.1 or CaV3.2
Retina: Conventional KO for CaV2.3 or CaV3.2, Conventional Double CaV2.3/CaV3.2 KO
Anesthesia: Conventional KO for CaV3.1, CaV3.2, or CaV3.3
Kidney Function: Conventional KO for CaV3.1 or CaV3.2
Lymphatic Vessel: Conventional KO for CaV3.1 or CaV3.2
Sperm: Conventional KO for CaV3.1 or CaV3.2
Mendelian Inheritance: Conventional KO for CaV2.3 or CaV3.2
References
Voltage-Gated Calcium Channels (VGCCs) and Synaptic Transmission
Introduction
VGCCs in Central Nerve Terminals
VGCCs and Interactive Proteins in AZs
RIMs
ELKS
MUNC 13
α- and β-liprins
Piccolo and Bassoon
SNAREs
VGCCs and Developmental Plasticity of Neurotransmitter Release
VGCCs and Short-Term Synaptic Plasticity
VGCCs and Synaptic Heterogeneity
Spatiotemporal Heterogeneity of Diverse Types of VGCCs
Morphological Modules of VGCC Clusters in Synaptic Heterogeneity
Conclusion
References
Functional Role and Plasticity of Voltage-Gated Calcium Channels in the Control of Heart Automaticity
Introduction
Role of VGCCs in the Generation of Cardiac Pacemaker Activity
Plasticity of Sinus Node Calcium Channels in Training
SAN VGCC in Ageing of the Sino-atrial Node
VGCCs in Sino-atrial Node Dysfunction Secondary to Heart Failure
Conclusions
References
An Integral View on Calcium Channels and Transporters Shaping Calcium and Exocytotic Signals in Chromaffin Cells
Introduction
Calcium Balance in Chromaffin Cells
Calcium Influx Through Voltage-Dependent Calcium Channels
Intracellular Calcium Movements
Cytosolic Calcium Buffers
Endoplasmic Reticulum
Mitochondria
Calcium Efflux
Calcium Movements and Exocytosis in Chromaffin Cells
Calcium Influx and Exocytosis
Cat Chromaffin Cells
Bovine Chromaffin Cells
Rat Chromaffin Cells
Mouse Chromaffin Cells
Dog Chromaffin Cells
Intracellular Calcium Movements and Exocytosis
Calcium Fluxes at the ER Calcium Store and Exocytosis
Mitochondrial Calcium Movements and Exocytosis
Calcium Efflux and Exocytosis
An Integrated View of Calcium and Exocytosis Signals in Chromaffin Cells
Subplasmalemmal High-Calcium Microdomains Are Required to Trigger Fast Exocytosis from Docked Vesicles
Termination of an Exocytotic Round by Dissipation of the High-Calcium Microdomain
Vesicle Flow Is Catalyzed by Low-Calcium Microdomains
An Integrated View of Calcium and Exocytosis in Adrenal Chromaffin Cells
Conclusions and Perspectives
References
Pancreatic β Cell CaV Channels in Health and Disease
Introduction
β Cell CaV Channels Under Healthy Circumstances
CaV Channel Regulation of Glucose-Stimulated Insulin Secretion
Involvement of CaV Channels in β Cell Maturity, Viability, and Expansion
CaV Channel-Centered Interaction Networks in the β Cell
CaV1 Channel-Exocytotic Protein Interaction Networks
CaVβ3 Subunit-InsP3 Receptor Signaling Pathway
CaVβ Subunit-PKC Signaling Pathway
β Cell CaV Channels in Pathology
Pathological Alterations of β Cell CaV Channel Phenotypes
Association of CaV Channel Gene Mutations and Polymorphisms with Abnormal Insulin Secretion and Diabetes
Engagement of CaV Channels in β Cell Dedifferentiation and Death
CaV Channels in β Cell Dedifferentiation
CaV Channels and β Cell Death
CaV Channel-Mediated Coupling of Diabetogenic Serum Components to Ca2+-Dependent β Cell Demise
Conclusions
References
The Skeletal Muscle Calcium Channel
Introduction
CaV1.1 Voltage Sensing
CaV1.1 in Skeletal Muscle Triads
Skeletal Muscle Excitation–Contraction Coupling
The (Enigmatic) Role of LTCC in Skeletal Muscle
The Structural Basis of CaV1.1 Function
Associated Proteins
Functionally Distinct CaV1.1 Isoforms
Structural Determinants of CaV1.1 Functions
The Structure of CaV1.1
Structure–Function Differences of CaV1.1 VSDs
CaV1.1 Channelopathies
Conclusion and Outlook
References
Cav1 L-Type Calcium Channels in the Auditory and Visual Systems
Introduction
Role of Cav1 Channels in Hearing and Vision
Cav1 Channel Family
Cav1 Channels in Hearing
Cav1 Channels in Vision
Regulation of Cav1.3 and Cav1.4 Functional Properties
Alternative Splicing
Cav1.3 and Cav1.4 Channel Interaction with Ca2+-Binding Proteins
Calmodulin (CaM)
CaBPs in Hair Cells and Photoreceptors
CaBPs in Other Retinal/Cochlear Cell-Types
Role of Cav1 Channels for the Development of the Visual and Hearing System
Cav1.3 Channels in Inner Hair Cell Maturation
Cav1.4 Channels in Photoreceptor Synapse Development
Channelopathies Affecting the Visual and Hearing System
Calcium Channelopathies in Hair Cells
Calcium Channelopathies in the Retina
Conclusion
References
Voltage-Gated Calcium Channels in the Afferent Pain Pathway
Introduction
N-Type Calcium Channels in the Afferent Pain Pathway
Interaction Between CRMP2 and Cav2.2: A Therapeutic Target for Chronic Pain
Cavα2δ Subunits and Neuropathic Pain
N-Type Channel Blockers as Pain Therapeutics
Opioid and GABA-B Receptor Regulation of N-Type Calcium Channels
Other Types of Cav2 Calcium Channels
Role of T-Type Calcium Channels in Afferent Pain Signaling
Dysregulation of Cav3.2 Channel Expression and Function in Chronic Pain States
T-Type Calcium Channel Blockers as Possible Pain Therapeutics
Conclusions
References
Voltage-Gated Calcium Channels and Migraine
Introduction
CaV2.1 Channels and Functional Consequences of FHM1 Mutations on Channel Biophysical Properties
Migraine-Relevant Phenotypes in FHM1 Mouse Models
Migraine-Relevant Alterations in the Cerebral Cortex of FHM1 Mouse Models
Alterations in the Trigeminovascular Pain Pathway in FHM1 Mouse Models
Conclusions
References
T-Type Calcium Channels in Epilepsy
Introduction
T-Type Calcium Channels and Temporal Lobe Epilepsy
Pilocarpine Model
Kainic Acid Model
Kindling Model
T-Type Channels and Absence Epilepsy
GAERS
WAG/Rij
T-Type Channel Mutations in Epilepsy
Conclusions
References
Novel Insights into the Role of Voltage-Gated Calcium Channel Genes in Psychiatric Disorders
Introduction
Overview of Psychiatric Disorders
Implications of Calcium Signaling in Psychiatric Disorders
Genetic Studies Linking VGCC Genes to Psychiatric Disorders
L-Type Channel Genes (CACNA1C and CACNA1D)
Presynaptic Calcium Channel Genes (CACNA1A, CACNA1B, CACNA1E)
T-Type Calcium Channel Genes (CACNA1G, CACNA1H, CACNA1I)
Calcium-Dependent Molecular Mechanisms in the Pathology of Psychiatric Disorders
L-Type Calcium Channels
Role of L-Type Channels in Altered Gene Expression in Psychiatric Disorders
Control of Neuronal Excitability by L-Type Channels in Psychiatric Disorders
Role of L-Type Channels in Neurogenesis in the Context of Psychiatric Disorders
Presynaptic Calcium Channels
Presynaptic Control of Transmitter Release and Psychiatric Disorders
Modulation by GPCRs
T-Type Channels and Control of Firing Frequency
Behavioral Roles of VGCCS in the Context of Psychiatric Disorders
VGCCs in Human Endophenotypes Associated with Psychiatric Disorders
VGCCs in Behavioral Assessments of Animal Models
VGCCs in Negative Valence Systems
VGCCs in Positive Valence Systems
VGCCs in Systems for Social Processes
VGCCs in Cognitive Systems
Targeting VGCCs to Treat Psychiatric Disorders
Conclusions
References
Calcium Channels and Selective Neuronal Vulnerability in Parkinson’s Disease
Parkinson’s Disease: A Multifactorial Disease
Selective Neuronal Vulnerability in Parkinson’s
Neuronal Phenotype and Ca2+ Signaling
Functions of Cav Channels in Vulnerable Neurons
The Linkage Between Cav Channels, Ca2+ Signaling and PD
Are Cav Channels Viable Therapeutic Targets for Disease Modification in PD?
Conclusions
References
Voltage-Dependent Calcium Channels (CaVs) and CatSper in Spermatogenic and Sperm Cells
Introduction
CaVs in Spermatogenic Cells and Sperm
Spermatogenesis
Calcium Channel Expression Within Sertoli and Spermatogenic Cells
CaVs in Sertoli Cells
T-type Ca2+ Channel in Spermatogenic Cells
Pharmacology of the Low Voltage Activated Ca2+ Current in Spermatogenic Cells
Other CaVs Channels in Spermatogenic Cells
Voltage-Gated Calcium Channel Regulation in Mammalian Germ Cell Line
Estradiol and Serum Albumin
Activation of Growth Hormone Secretagogue Type 1a Receptor
Arachidonic Acid
Calmodulin
Tyrosine Phosphorylation
Functional Roles of CaVs
Chemotaxis
Do CaVs Participate in Sea Urchin Sperm Chemotaxis?
Acrosome Reaction (AR)
CatSper Channels
Expression in Different Mammalian Species
Molecular Composition, Biophysical Properties, Regulation, and Pharmacology
CatSper Regulation
Vm Regulation
pH Regulation
HCO3− Regulation
Hormone Regulation
Progesterone
Other Steroid Hormones: Testosterone, Estrogen, and Cortisol
Prostaglandins
Other CatSper Regulatory Factors from Seminal Fluid and Female Reproductive Tract
Zinc
Glycoproteins
Cysteine-Rich Secretory Proteins (CRISP)
Environmental Factors
Cyclic Nucleotides
CatSper Channel Blockers
Chemotaxis
Hyperactivation
Rheotaxis
Acrosomal Reaction (AR)
Conclusions and Perspectives
References
Voltage-Gated Calcium Channels as Key Regulators of Cancer Progression
Introduction
Altered VGCC Expression in Cancer
Cav1.X Family
Cav2.X Family
Cav3.X Family
α2δ Subunits
β Subunits
γ Subunits
Functional Consequences of VGCC Expression in Cancer
Tumour Growth and Proliferation
Hypoxia and Angiogenesis
Apoptosis and Chemotherapy Resistance
Differentiation
Migration and Invasion
Targeting VGCCs in Cancer: Evidence from Clinical Studies
Concluding Remarks
References
Part IV: Pharmacology of VGCCs
Pharmacology of Voltage-Gated Calcium Channels at Atomic Resolution
Calcium Channel Pharmacology
State-Dependent Drug Block of CaV1 Channels
Drug Receptor Sites for State-Dependent Block of Calcium Channels
Structures of the Drug Receptor Sites on CaVAb Channels
Structures of the Drug Receptor Sites on CaV1.1 Channels
Neurotoxin Receptor Sites on CaV2 Channels
Structure of the CaV2.2 Complex with Ziconotide
Drugs Acting on the Auxiliary α2 Subunits of CaV2 Channels
Drug Receptor Sites on CaV3 Channels
Conclusion
References
Pharmacology and Structure-Function of Venom Peptide Inhibitors of N-Type (Cav2.2) Calcium Channels
Introduction
Selective CaV2.2 Inhibitors
Non-selective CaV2.2 Inhibitors
Structure-Activity Studies of ω-Conotoxins at CaV2.2
Conclusions
References
From Calcium Channels to New Therapeutics
Nifedipine
Gabapentin and Pregabalin
Ziconotide
Learnings and Emerging Resources for Drug Development
Experimental Therapeutics
Conclusions
References
Index