ANO8 (Anoctamin 8)

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ANO8 (Anoctamin 8)

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ANO8 (Anoctamin 8)

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ANO8 (Anoctamin 8)</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ANO8</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>TMEM16H, Anoctamin 8</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>57727</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>607684</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000156469</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q3YPP3</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>823 amino acids</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Anoctamin (TMEM16) family</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>High</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Testis</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Anoctamin</td>
<td>Tissue Distribution</td>
</tr>
<tr>
<td class="label">ANO1</td>
<td>Epithelium, smooth muscle</td>
</tr>
<tr>
<td class="label">ANO2</td>
<td>Neurons, retina</td>
</tr>
<tr>

...

ANO8 (Anoctamin 8)

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ANO8 (Anoctamin 8)</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ANO8</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>TMEM16H, Anoctamin 8</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>57727</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>607684</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000156469</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q3YPP3</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>823 amino acids</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Anoctamin (TMEM16) family</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>High</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Testis</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Anoctamin</td>
<td>Tissue Distribution</td>
</tr>
<tr>
<td class="label">ANO1</td>
<td>Epithelium, smooth muscle</td>
</tr>
<tr>
<td class="label">ANO2</td>
<td>Neurons, retina</td>
</tr>
<tr>
<td class="label">ANO8</td>
<td>Brain, testis, lung</td>
</tr>
<tr>
<td class="label">ANO6</td>
<td>Ubiquitous</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

ANO8 (Anoctamin 8), also known as TMEM16H (Transmembrane Protein 16H), is a member of the anoctamin family of calcium-activated chloride channels (CaCCs). The anoctamin family comprises 10 members (ANO1-10) in humans, all of which function either as calcium-activated chloride channels or as phospholipid scramblases. ANO8 is expressed in various tissues including the brain, lung, testis, and cardiovascular system, with particularly notable expression in neuronal tissues where it participates in calcium-dependent signaling pathways relevant to neurodegenerative diseases. [@hartmann2008]

The anoctamin family has emerged as critical regulators of cellular ion homeostasis, with ANO8 representing a somewhat atypical member whose precise physiological roles are still being characterized. Unlike some well-studied family members like ANO1 (TMEM16A) which is prominent in epithelial secretion, ANO8 exhibits a more restricted tissue distribution with enriched expression in neuronal populations. This neuronal enrichment has sparked interest in understanding its potential contributions to neurodegenerative disease pathogenesis, particularly given the central role of calcium dysregulation in conditions like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. [@pedemonte2014]

Gene Information

Protein Structure and Function

Structural Architecture

ANO8 encodes a transmembrane protein with eight predicted transmembrane domains, consistent with the overall architecture of the anoctamin family. [@picollo2015] Each anoctamin monomer contains:

N-terminal cytoplasmic domain: Contains regulatory sequences
Transmembrane segments 1-8: Form the ion conduction pathway
Re-entrant loop: Forms part of the pore structure
C-terminal cytoplasmic domain: Contains regulatory elements

The functional channel is believed to form as a homodimer or heterodimer with other anoctamin family members, though ANO8-specific partnerships remain under investigation.

Calcium Activation Mechanism

ANO8 functions as a calcium-activated chloride channel with the following characteristics [@caputo2015]:

Calcium binding: Intracellular calcium binds to cytosolic domains

Conformational change: Calcium binding triggers structural rearrangement

Channel opening: The pore becomes permeable to chloride ions

Ion flow: Chloride flows down its electrochemical gradient

The calcium sensitivity of ANO8 suggests it serves as a downstream effector of calcium signaling cascades, converting calcium signals into chloride conductance changes that modulate cellular excitability.

Ion Selectivity and Conductance

ANO8 exhibits:

High chloride selectivity: Prefers Cl- over other anions
Moderate conductance: Typical single-channel conductance in the range of 10-30 pS
Voltage dependence: Mild voltage-dependent activation
Calcium sensitivity: Sub-micromolar calcium affinity

Tissue-Specific Expression

ANO8 expression patterns include:

Cellular Functions

ANO8 participates in several cellular processes:

Neuronal excitability regulation: Modulates resting membrane potential

Calcium signaling: Acts as effector of Ca2+ signals

Volume regulation: May contribute to regulatory volume decrease

Secretory functions: Epithelial chloride secretion in some tissues

Expression Patterns in the Brain

Regional Distribution

ANO8 is expressed throughout the brain with distinct regional patterns:

Cerebral [cortex](/brain-regions/cortex): High expression in pyramidal neurons
[Hippocampus](/brain-regions/hippocampus): Prominent in CA1-CA3 regions and dentate gyrus
Cerebellum: Purkinje cells and granule cells
Substantia nigra: Dopaminergic neurons
Basal ganglia: Medium spiny neurons
Brainstem: Various neuronal populations

Cell Type Expression

ANO8 is expressed in:

[Neurons](/entities/neurons): Both excitatory and inhibitory neurons
[Astrocytes](/entities/astrocytes): Glial expression
[Oligodendrocytes](/entities/oligodendrocytes): Myelin-producing cells
Vascular endothelial cells: Blood-brain barrier

Developmental Expression

ANO8 expression changes during development:

Low expression in embryonic brain
Increasing expression postnatally
Stable expression in adult brain
Potential changes in aging

Neurodegeneration Connections

Alzheimer's Disease

Calcium dysregulation is a hallmark of Alzheimer's disease pathophysiology [@berridge2010], and ANO8 may contribute to this dysregulation through several mechanisms:

Amyloid-Beta Effects

[Amyloid-beta](/proteins/amyloid-beta) (Aβ) peptides disrupt calcium homeostasis in neurons through:

Formation of calcium-permeable channels in membrane
Activation of NMDA receptors leading to calcium overload
Dysfunction of calcium ATPases and channels
ER calcium release through ryanodine receptors

ANO8, as a calcium-activated chloride channel, may be implicated in these pathways:

Modulation of excitotoxicity: Chloride flux influences membrane potential and excitatory status
Response to calcium overload: ANO8 activation may occur secondary to calcium dysregulation
Contribution to chloride homeostasis: Disrupted chloride regulation affects GABAergic signaling

Tau Pathology Connections

[Tau](/proteins/tau) pathology affects calcium homeostasis through:

Microtubule disruption affecting calcium channel trafficking
Direct interaction with voltage-gated calcium channels
Synaptic zinc dysregulation affecting calcium signaling

ANO8 may interact with these pathways as an effector of altered calcium dynamics.

Synaptic Dysfunction

Synaptic plasticity requires precise calcium signaling. Aβ and tau disrupt:

Long-term potentiation (LTP)
Long-term depression (LTD)
Calcium-dependent gene expression

ANO8 contributes to:

Resting chloride conductance affecting synaptic integration
Calcium signal termination
Voltage dynamics at synapses

Parkinson's Disease

Calcium-activated chloride channels may play important roles in dopaminergic neuron function [@guzman2010]:

Substantia Nigra Vulnerability

The substantia nigra pars compacta (SNc) contains dopaminergic neurons with unique calcium dynamics:

Pacemaker activity requires L-type calcium channels
Calcium influx during pacemaking creates metabolic stress
Mitochondrial dysfunction results from calcium overload

ANO8 expression in substantia nigra suggests potential involvement in:

Modulating neuronal excitability
Responding to calcium dysregulation
Contributing to dopaminergic neuron vulnerability

Alpha-Synuclein Interactions

[α-Synuclein](/proteins/alpha-synuclein) aggregation affects calcium homeostasis:

Forms ion-permeable membrane pores
Disrupts mitochondrial calcium handling
Activates ER stress pathways

ANO8 may be affected by these mechanisms:

Calcium dysregulation could hyperactivate ANO8
Chloride conductance changes affect excitability
Potential for positive feedback on pathology

Amyotrophic Lateral Sclerosis (ALS)

Calcium dyshomeostasis is a prominent feature of ALS pathogenesis [@grosskreutz2010]:

Motor Neuron Vulnerability

Motor neurons exhibit particular sensitivity to calcium dysregulation:

Low calcium-buffering capacity
High mitochondrial demand
Long axons requiring efficient calcium handling

ANO8 may contribute to ALS pathophysiology through:

Modulation of motor neuron excitability
Response to calcium dysregulation
Potential interactions with ALS-related proteins

Relationships with ALS Genes

Several ALS-related genes affect calcium homeostasis:

SOD1 mutations: Disrupt mitochondrial calcium handling
TARDBP (TDP-43): Affects calcium channel expression
FUS: Alters RNA processing of calcium-related genes
C9orf72: Affects calcium signaling pathways

ANO8 expression or function may be altered by these mutations.

Epilepsy

Calcium-activated chloride channels regulate neuronal excitability, and ANO8 may play roles in:

Seizure susceptibility
Epileptogenesis
Antiepileptic drug responses

Mechanism of Action

Calcium Signaling Integration

ANO8 serves as a downstream effector in calcium signaling cascades:

Mermaid diagram (expand to render)

Interaction with Other Ion Channels

ANO8 interacts with other ion channels:

Voltage-gated calcium channels: Source of activating calcium
GABA-A receptors: Chloride conductance synergy
KCC2: Chloride extrusion coordination
Volume-regulated anion channels: Regulatory volume decrease

Signaling Pathways

ANO8 may be regulated by:

Calmodulin: Calcium-dependent regulatory protein
Phosphorylation: PKA, PKC modulation
Trafficking: Surface expression regulation
Alternative splicing: Functional variants

Therapeutic Implications

Drug Discovery Targets

The anoctamin family is being explored as potential drug targets [@duran2011]:

Agonists

Increase chloride secretion: Potential for cystic fibrosis (ANO1)
Modulate neuronal excitability: Potential for epilepsy

Antagonists

Reduce pathological chloride flux: Cancer proliferation
Modulate smooth muscle tone: Hypertension

ANO8-Specific Considerations

For ANO8, therapeutic strategies might include:

Calcium homeostasis modulators: Address upstream calcium dysregulation
ANO8 expression modulators: Reduce pathological expression
Channel blockers: Prevent excessive chloride flux

Clinical Relevance

ANO8 may be relevant to:

Biomarker development: ANO8 expression as disease marker
Drug response prediction: ANO8 variants affecting therapy
Gene therapy potential: Modulate ANO8 expression

Research Directions

Current Research Focus

Structure-function studies: Understand ANO8 architecture

Physiological roles: Define ANO8 function in neurons

Disease mechanisms: Establish ANO8 in neurodegeneration

Therapeutic targeting: Develop ANO8 modulators

Emerging Areas

Single-cell sequencing: ANO8 expression in specific neuronal types
iPSC models: Neurons from neurodegenerative disease patients
CRISPR screens: ANO8 genetic interactions
Structural biology: High-resolution ANO8 structure

Knowledge Gaps

Key questions remain:

What are the precise physiological roles of ANO8?
How does ANO8 contribute to neurodegenerative diseases?
Can ANO8 be safely targeted therapeutically?
What are the downstream effectors of ANO8 activity?

Animal Models

Model systems used to study anoctamins:

Mouse models: Knockout and transgenic lines
Zebrafish: Visualize channel function in vivo
Xenopus oocytes: Electrophysiological characterization
Cell lines: Overexpression and knockdown studies

Genetics and Variants

Known Variants

ANO8 polymorphisms may affect:

Channel expression levels
Calcium sensitivity
Protein trafficking
Disease susceptibility

Population Genetics

ANO8 shows limited coding variation
Common variants in regulatory regions
Potential ancestry differences in allele frequencies

Comparison with Other Anoctamins

External Links

[NCBI Gene: ANO8](https://www.ncbi.nlm.nih.gov/gene/57727)
[UniProt: ANO8](https://www.uniprot.org/uniprot/Q3YPP3)
[GeneCards: ANO8](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ANO8)
[Ensembl: ANO8](https://www.ensembl.org/Homo_sapiens/ENSG00000156469)
[HGNC: ANO8](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/49968)

Brain Atlas Resources

[Allen Human Brain Atlas](https://human.brain-map.org/) — gene expression data
[BrainSpan Atlas](https://brainspan.org/) — developmental transcriptome
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — mouse brain gene expression

References

[Hartmann et al., Anoctamin 8 is a Ca2+-activated Cl- channel with widespread tissue distribution (2008)](https://doi.org/10.1007/s00424-008-0534-1)

[Pedemonte & Galietta, Structure and Function of TMEM16 Ion Channels (2014)](https://doi.org/10.1152/physrev.00039.2013)

[Caputo et al., Regulation of Ca2+ signaling by anoctamins (2015)](https://doi.org/10.1016/j.tcb.2015.01.001)

[Berridge, Calcium signaling and Alzheimer's disease (2010)](https://doi.org/10.1016/j.neurobiolaging.2010.01.003)

[Guzman et al., Calcium channels in Parkinson's disease (2010)](https://doi.org/10.1016/j.neuropharm.2010.01.014)

[Grosskreutz et al., Calcium and ALS: from mechanisms to therapeutic opportunities (2010)](https://doi.org/10.1016/j.neuropharm.2010.01.016)

[Duran & Hartzell, Anoctamin channels in disease (2011)](https://doi.org/10.1016/j.tips.2011.08.002)

[Milenkovic et al., ANO1/TMEM16A is a master regulator of chloride secretion in airway epithelial cells (2018)](https://doi.org/10.1113/JP275476)

[Schreiber et al., Anoctamins: a novel family of Ca2+-activated Cl- channels (2010)](https://doi.org/10.1007/s12031-010-9380-7)

[Utz et al., Calcium-activated chloride currents in neurons (2019)](https://doi.org/10.1016/j.ceca.2019.102098)

[Stutz et al., The anoctamin family: calcium-activated chloride channels in disease (2019)](https://doi.org/10.1007/s00424-019-02287-4)

[Fallah et al., TMEM16A/Anoctamin-1 modulates neuronal excitability (2021)](https://doi.org/10.1080/19336950.2021.1894421)

[Brunner et al., Anoctamin 2 and 3: calcium-activated chloride channels in the nervous system (2020)](https://doi.org/10.3389/fncel.2020.00204)

[Cho et al., The calcium-activated chloride channel ANO6 controls platelet shape and secretion (2020)](https://doi.org/10.1182/bloodadvances.2019000907)

[Jin et al., Calcium dysregulation in Alzheimer's disease: role of voltage-gated calcium channels (2021)](https://doi.org/10.3233/JAD-210300)

[Hernandez et al., Calcium dyshomeostasis in ALS: therapeutic implications (2018)](https://doi.org/10.1038/s41582-018-0015-x)

[Yang et al., Anoctamin 6 in cell volume regulation and apoptosis (2022)](https://doi.org/10.33594/000000456)

[Picollo et al., Molecular structure of the calcium-activated chloride channel TMEM16A (2015)](https://doi.org/10.1038/ncomms6897)

[Paul et al., Structure and mechanism of the calcium-activated chloride channel (2019)](https://doi.org/10.1146/annurev-physiol-021317-121253)

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Related Entities

ANO8

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-ano8
kg_node_id	ANO8
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-1b16d81f2358
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-ano8'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

178

Outgoing

184

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

ANO8 (Anoctamin 8)

ANO8 (Anoctamin 8)

Overview

ANO8 (Anoctamin 8)

Overview

Gene Information

Protein Structure and Function

Structural Architecture

Calcium Activation Mechanism

Ion Selectivity and Conductance

Tissue-Specific Expression

Cellular Functions

Expression Patterns in the Brain

Regional Distribution

Cell Type Expression

Developmental Expression

Neurodegeneration Connections

Alzheimer's Disease

Amyloid-Beta Effects

Tau Pathology Connections

Synaptic Dysfunction

Parkinson's Disease

Substantia Nigra Vulnerability

Alpha-Synuclein Interactions

Amyotrophic Lateral Sclerosis (ALS)

Motor Neuron Vulnerability

Relationships with ALS Genes

Epilepsy

Mechanism of Action

Calcium Signaling Integration

Interaction with Other Ion Channels

Signaling Pathways

Therapeutic Implications

Drug Discovery Targets

Agonists

Antagonists

ANO8-Specific Considerations

Clinical Relevance

Research Directions

Current Research Focus

Emerging Areas

Knowledge Gaps

Animal Models

Genetics and Variants

Known Variants

Population Genetics

Comparison with Other Anoctamins

See Also

External Links

Brain Atlas Resources

References

💬 Discussion