Receptor, Transporter and Ion Channel Diseases

Gargus, J. Jay

doi:10.1002/3527600906.mcb.200400158

Cited by 3 publications

(21 citation statements)

References 196 publications

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“…The standing electrochemical gradients that drive passive ion movements though channels are established by energy dependent active transport mechanisms such as ion pumps and ion carriers (Gargus, 2008). Ion channels conduct ions four orders of magnitude faster than pumps and carriers, so in many ways channels act like highly selective water filled pores that can be opened and closed in a controlled fashion (gated) to allow a specific ion species to flow.…”

Section: Defective Channel Function In Autismmentioning

confidence: 99%

“…It is therefore not surprising that a diverse host of diseases are coming to be recognized to be caused by disruptions of intracellular calcium homeostasis. This is an emerging pathophysiological mechanism of disease, a calciumopathy (Stutzmann et al, 2006; Bezprozvanny and Gargus, 2008; Betzenhauser and Marks, 2010; Feske, 2010; Cain and Snutch, 2011), a special subset of the ion channel channelopathy diseases (Gargus, 2003, 2008, 2009). …”

Section: Defective Channel Function In Autismmentioning

confidence: 99%

“…The typical channelopathy lesions in well-understood monogenic diseases of heart, muscle and nerve cause membrane hyper-excitability . Hence, mutations in Ca 2 + and Na + channels, which physiologically excite a tissue, typically have gain-of-function lesions, while mutations in K + and Cl - channels, which physiologically stabilize excitable tissue, typically have pathological lesions that diminish their current (Gargus, 2008). …”

Section: The Impact Of Mutations In Other Calcium Channel Subunits Inmentioning

confidence: 99%

“…The monogenic seizure and migraine diseases are all caused by ion channel mutations and have a common channelopathy pathogenesis (Dodick and Gargus, 2008). The mutations all produce constitutionally hyper-excitable neurons that are susceptible to “arrhythmias” or periodic decompensations, much like the LQT heart or the MHS-periodically paralyzed muscle (Gargus, 2006, 2008, 2009). For example, the gene families ( FHM1/CACNA1A, FHM2/ATP1A2 and FHM3/SCN1A ), the mutational lesions and the integrated pathophysiology underlying FHM3, are all strikingly homologous to those in epilepsy, LQT and MHS, and provide a robust platform for understanding the pathogenesis of the calcium channel autism syndrome, TS/LQT8.…”

Section: Family Of Autism-related Diseases With Defective Neuronal Camentioning

confidence: 99%

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Channelopathy pathogenesis in autism spectrum disorders

Schmunk¹,

Gargus²

2013

Front. Genet.

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106

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Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies) in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders. Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.

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Section: Defective Channel Function In Autismmentioning

confidence: 99%

Section: Defective Channel Function In Autismmentioning

confidence: 99%

Section: The Impact Of Mutations In Other Calcium Channel Subunits Inmentioning

confidence: 99%

Section: Family Of Autism-related Diseases With Defective Neuronal Camentioning

confidence: 99%

See 2 more Smart Citations

Channelopathy pathogenesis in autism spectrum disorders

Schmunk¹,

Gargus²

2013

Front. Genet.

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106

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“…Cytosolic calcium signals originate either as extracellular calcium enters the cell through plasma membrane ion channels, or originate from the release of an intracellular store in the endoplasmic reticulum (ER) through ER inositol triphosphate receptor (IP3R) and ryanodine receptor (RyR) channels. Therefore, to a large extent the calcium diseases represent a subset of the channelopathies , that relatively new class of diseases caused by defects in ion transporters such as ion pumps and channels 3,4 . A number of classic channelopathies arise from mutations in either plasmalemmal or ER calcium channels, for instance, malignant hyperthermia (MHS), where MHS1 is caused by ryanodine receptor mutations ( RYR1) and MHS5 is caused by voltage‐gated calcium channel mutations ( CACNA1S) .…”

Section: Calciumopathies: Calcium Signaling Diseasesmentioning

confidence: 99%

Genetic Calcium Signaling Abnormalities in the Central Nervous System: Seizures, Migraine, and Autism

Gargus

2008

Annals of the New York Academy of Sciences

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110

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The calcium ion is one of the most versatile, ancient, and universal of biological signaling molecules, known to regulate physiological systems at every level from membrane potential and ion transporters to kinases and transcription factors. Disruptions of intracellular calcium homeostasis underlie a host of emerging diseases, the calciumopathies. Cytosolic calcium signals originate either as extracellular calcium enters through plasma membrane ion channels or from the release of an intracellular store in the endoplasmic reticulum (ER) via inositol triphosphate receptor and ryanodine receptor channels. Therefore, to a large extent, calciumopathies represent a subset of the channelopathies, but include regulatory pathways and the mitochondria, the major intracellular calcium repository that dynamically participates with the ER stores in calcium signaling, thereby integrating cellular energy metabolism into these pathways, a process of emerging importance in the analysis of the neurodegenerative and neuropsychiatric diseases. Many of the calciumopathies are common complex polygenic diseases, but leads to their understanding come most prominently from rare monogenic channelopathy paradigms. Monogenic forms of common neuronal disease phenotypes-such as seizures, ataxia, and migraine-produce a constitutionally hyperexcitable tissue that is susceptible to periodic decompensations. The gene families and genetic lesions underlying familial hemiplegic migraine, FHM1/CACNA1A, FHM2/ATP1A2, and FHM3/SCN1A, and monogenic mitochondrial migraine syndromes, provide a robust platform from which genes, such as CACNA1C, which encodes the calcium channel mutated in Timothy syndrome, can be evaluated for their role in autism and bipolar disease.

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Monogenic migraine syndromes highlight novel drug targets

Gargus

Shih

2007

Drug Development Research

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In the post‐genomic era, the paradigm for drug discovery has changed, as every gene may become a potential target. Genetic diseases provide a special window into gene target selection. This approach is being applied to migraine making use of the genes and mutations causing familial hemiplegic migraine (FHM). FHM is caused by missense mutations in CACNA1A, altering a neuronal P/Q Ca2+ channel, in ATP1A2, altering α2 Na,K‐ATPase, and in SCN1A, altering a neuronal sodium channel. These genes provide insights into migraine pathogenesis that likely extend to other forms of migraine as well. Since the three FHM genes are only co‐expressed in neurons, FHM is a neuronal, not a vascular, disease and because they all encode ion transport proteins, FHM is a neuronal channelopathy—meaning meta‐stable neuronal hyperexcitability is the substrate of migraine, much as it is for genetic epilepsy syndromes. This similarity is reinforced, since different mutations of all three FHM genes can produce seizure syndromes. This has implications for drug discovery in that seizure medications already known to modulate the FHM channel mechanisms warrant more targeted development, and that drugs targeted to vascular headaches, such as the historically effective triptans, or experimental botulinum toxin, may well work by similar nonvascular mechanisms. Finally, in model neurogenetic systems such as Caenorhabditis elegans, the FHM genes also provide both a comprehensive means to discover all genes involved in their signaling pathway—genes potentially involved in common forms of the disease, and an in vivo whole animal means to screen rapidly for novel therapeutics. Drug Dev Res 68:432–440, 2007. © 2008 Wiley‐Liss, Inc.

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Receptor, Transporter and Ion Channel Diseases

Cited by 3 publications

References 196 publications

Channelopathy pathogenesis in autism spectrum disorders

Channelopathy pathogenesis in autism spectrum disorders

Genetic Calcium Signaling Abnormalities in the Central Nervous System: Seizures, Migraine, and Autism

Monogenic migraine syndromes highlight novel drug targets

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