Details for: TMEM38A

Gene ID: 79041

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: TMEM38A

Ensembl ID: ENSG00000072954

Description: transmembrane protein 38A

Cell Significance Landscape

Associated with

  • Cellular response to caffeine
    (GO:0071313)
  • Endoplasmic reticulum organization
    (GO:0007029)
  • Extracellular exosome
    (GO:0070062)
  • Identical protein binding
    (GO:0042802)
  • Metal ion binding
    (GO:0046872)
  • Nuclear membrane
    (GO:0031965)
  • Potassium channel activity
    (GO:0005267)
  • Potassium ion transmembrane transport
    (GO:0071805)
  • Regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion
    (GO:0010881)
  • Regulation of release of sequestered calcium ion into cytosol
    (GO:0051279)
  • Release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    (GO:0014808)
  • Sarcoplasmic reticulum membrane
    (GO:0033017)

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • L6b glutamatergic cortical neuron CL4023038
    CSI 3.77
    rCSI 11.79%
    PRS 85.01
  • renal alpha-intercalated cell CL0005011
    CSI 3.42
    rCSI 4.58%
    PRS 95.71
  • ionocyte CL0005006
    CSI 3.12
    rCSI 3.35%
    PRS 94.7
  • ependymal cell CL0000065
    CSI 3.08
    rCSI 6.26%
    PRS 79.14
  • interneuron CL0000099
    CSI 3.07
    rCSI 6.16%
    PRS 89.3
  • choroid plexus epithelial cell CL0000706
    CSI 2.95
    rCSI 4.83%
    PRS 88.43
  • Mueller cell CL0000636
    CSI 2.8
    rCSI 6.39%
    PRS 88.68
  • rod bipolar cell CL0000751
    CSI 2.77
    rCSI 4.98%
    PRS 89.9
  • vascular leptomeningeal cell CL4023051
    CSI 2.74
    rCSI 4.8%
    PRS 91.46
  • pulmonary ionocyte CL0017000
    CSI 2.61
    rCSI 3.18%
    PRS 96.03
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.43
    rCSI 3.13%
    PRS 85
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.42
    rCSI 3.01%
    PRS 81.94
  • cardiac muscle cell CL0000746
    CSI 2.19
    rCSI 3.14%
    PRS 87.16
  • amacrine cell CL0000561
    CSI 2.19
    rCSI 6.33%
    PRS 87.18
  • foveolar cell of stomach CL0002179
    CSI 2.15
    rCSI 4.58%
    PRS 94.91
  • cerebral cortex neuron CL0010012
    CSI 2.13
    rCSI 8.67%
    PRS 87.88
  • muscle cell CL0000187
    CSI 2.06
    rCSI 4.23%
    PRS 95.09
  • inhibitory interneuron CL0000498
    CSI 2.05
    rCSI 4.74%
    PRS 86.81
  • renal beta-intercalated cell CL0002201
    CSI 2.04
    rCSI 4.86%
    PRS 94.2
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 2.03
    rCSI 6.34%
    PRS 86.78
  • VIP GABAergic cortical interneuron CL4023016
    CSI 1.98
    rCSI 2.37%
    PRS 84.06
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 1.88
    rCSI 4.51%
    PRS 85.59
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 1.86
    rCSI 10.97%
    PRS 84.36
  • retinal bipolar neuron CL0000748
    CSI 1.81
    rCSI 3.4%
    PRS 87.34
  • fast muscle cell CL0000190
    CSI 1.79
    rCSI 7.01%
    PRS 87.15
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.64
    rCSI 3.68%
    PRS 84.28
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.62
    rCSI 2.72%
    PRS 84.17
  • retinal pigment epithelial cell CL0002586
    CSI 1.6
    rCSI 3.18%
    PRS 91.02
  • retinal cone cell CL0000573
    CSI 1.6
    rCSI 2.57%
    PRS 87.4
  • central nervous system neuron CL2000029
    CSI 1.56
    rCSI 11.48%
    PRS 87.8
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.52
    rCSI 2.45%
    PRS 85.06
  • direct pathway medium spiny neuron CL4023026
    CSI 1.48
    rCSI 35.45%
    PRS 81.9
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 1.47
    rCSI 3.19%
    PRS 84.46
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.44
    rCSI 2.54%
    PRS 83.5
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.4
    rCSI 33.72%
    PRS 81.86
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.38
    rCSI 3.35%
    PRS 81.9
  • kidney connecting tubule epithelial cell CL1000768
    CSI 1.23
    rCSI 3.11%
    PRS 89.7
  • GABAergic neuron CL0000617
    CSI 1.19
    rCSI 3.98%
    PRS 82.8
  • retinal ganglion cell CL0000740
    CSI 1.16
    rCSI 2.56%
    PRS 85.65
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 1.06
    rCSI 3.8%
    PRS 82.22
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 1.05
    rCSI 3.45%
    PRS 84.42
  • regular ventricular cardiac myocyte CL0002131
    CSI 0.97
    rCSI 6.08%
    PRS 88.55
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 0.89
    rCSI 3.35%
    PRS 84.19
  • dopaminergic neuron CL0000700
    CSI 0.79
    rCSI 4.48%
    PRS 85.25
  • medium spiny neuron CL1001474
    CSI 0.51
    rCSI 4.42%
    PRS 87.61
  • ON parasol ganglion cell CL4033052
    CSI 0.47
    rCSI 6.62%
    PRS 87.66

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [TMEM38A](/details-gene/79041) (Transmembrane protein 38A) encodes a component of the trimeric intracellular cation (TRIC) channel, which is crucial for ion homeostasis within intracellular stores. The protein functions as a potassium channel involved in the regulation of sequestered calcium ion release from the endoplasmic and sarcoplasmic reticulum ([Link](https://doi.org/10.1038/nature05928)). Its expression pattern is highly specialized, showing significant enrichment in excitable cells and specialized ion-transporting epithelial cells. **Overall**, the data highlight its critical role in cells that rely on precise ion gradients for their function, including neurons such as the [L6b glutamatergic cortical neuron](/details-cell/CL4023038), epithelial ionocytes like the [renal alpha-intercalated cell](/details-cell/CL0005011), and contractile cells like the [cardiac muscle cell](/details-cell/CL0000746). ## Cellular Roles and Expression Landscape The expression profile of [TMEM38A](/details-gene/79041) suggests a fundamental role in maintaining electrochemical gradients across a specific set of cell types. **Overall**, its significance is highest in tissues characterized by high metabolic activity and ion flux. A prominent feature is its high significance in the central nervous system. The gene is a key marker for diverse neuronal subtypes, including [L6b glutamatergic cortical neuron](/details-cell/CL4023038) (CSI: 3.77), [interneuron](/details-cell/CL0000099) (CSI: 3.07), [sst GABAergic cortical interneuron](/details-cell/CL4023017) (CSI: 2.43), and [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) (CSI: 2.42). It is also highly significant in retinal neurons like the [rod bipolar cell](/details-cell/CL0000751) and [amacrine cell](/details-cell/CL0000561), as well as glial-like [Mueller cell](/details-cell/CL0000636)s. This widespread expression across neuronal populations points to a general role in neuronal function, likely related to regulating intracellular calcium stores essential for neurotransmission and cellular excitability. Beyond the nervous system, [TMEM38A](/details-gene/79041) is a defining marker for specialized epithelial cells responsible for ion transport. This includes high significance in [renal alpha-intercalated cell](/details-cell/CL0005011) (CSI: 3.42), [ionocyte](/details-cell/CL0005006) (CSI: 3.12), and [pulmonary ionocyte](/details-cell/CL0017000) (CSI: 2.61), which are critical for acid-base and electrolyte balance. Its expression in [choroid plexus epithelial cell](/details-cell/CL0000706) and [ependymal cell](/details-cell/CL0000065) further underscores its involvement in regulating the ionic composition of biological fluids, in this case, the cerebrospinal fluid. Finally, its significant expression in [cardiac muscle cell](/details-cell/CL0000746) (CSI: 2.19) is consistent with its established role in excitation-contraction coupling through calcium handling in the sarcoplasmic reticulum. ## Pathways and Molecular Function Functional annotation confirms that [TMEM38A](/details-gene/79041) is integral to ion transport and intracellular signaling. Its primary molecular function is described as [Potassium channel activity](/details-go/GO:0005267), contributing to its role as an ion channel ([Link](https://doi.org/10.1038/s12276-024-01206-1)). This activity is essential for several biological processes, most notably the [Regulation of release of sequestered calcium ion into cytosol](/details-go/GO:0051279) and [Potassium ion transmembrane transport](/details-go/GO:0071805). The gene's product is a key component of the TRIC channel, which acts as a counter-ion channel to facilitate the rapid release of calcium from intracellular stores like the endoplasmic and sarcoplasmic reticulum. This mechanism is critical for [Regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion](/details-go/GO:0010881), directly explaining its importance in [cardiac muscle cell](/details-cell/CL0000746)s. The process of [Release of sequestered calcium ion into cytosol by sarcoplasmic reticulum](/details-go/GO:0014808) is a universal signaling mechanism, consistent with the gene's high significance in neurons where ER calcium stores modulate synaptic plasticity and firing patterns. The protein primarily localizes to the [Sarcoplasmic reticulum membrane](/details-go/GO:0033017) and [Nuclear membrane](/details-go/GO:0031965), placing it at key sites of intracellular calcium regulation. ## Research Directions The highly specific expression pattern and critical function of [TMEM38A](/details-gene/79041) in ion homeostasis present several avenues for future research, particularly concerning channelopathies and diseases of excitable tissues. ### Proposed Hypotheses: 1. **Neuronal Excitability:** Given its high significance in a wide array of neurons ([L6b glutamatergic cortical neuron](/details-cell/CL4023038), [interneuron](/details-cell/CL0000099)), we hypothesize that variants or dysregulation of [TMEM38A](/details-gene/79041) contribute to neurological disorders characterized by neuronal hyperexcitability, such as epilepsy. A compromised ability to regulate ER calcium stores could disrupt neuronal firing thresholds and synaptic transmission. 2. **Epithelial Transport Disorders:** Its prominent expression in specialized cells like [renal alpha-intercalated cell](/details-cell/CL0005011) and [pulmonary ionocyte](/details-cell/CL0017000) suggests a role in systemic electrolyte balance. We hypothesize that loss-of-function mutations in [TMEM38A](/details-gene/79041) could underlie certain forms of renal tubular acidosis or contribute to the pathophysiology of diseases with defective ion transport, like cystic fibrosis, by impairing the function of these critical cell types. ### Key Experiment: To test the hypothesis regarding neuronal excitability, a targeted knockout of [TMEM38A](/details-gene/79041) could be generated in a mouse model using CRISPR-Cas9. Primary cortical neurons would be isolated from knockout and wild-type littermates. Electrophysiological properties would be assessed using whole-cell patch-clamp to measure changes in resting membrane potential, action potential frequency in response to current injection, and the properties of spontaneous excitatory and inhibitory postsynaptic currents. Furthermore, calcium imaging using fluorescent indicators (e.g., Fura-2) would be employed to directly measure the dynamics of calcium release from ER stores following stimulation, providing a direct link between the channel's function and neuronal signaling. ### Therapeutic Potential: As a transmembrane ion channel, [TMEM38A](/details-gene/79041) represents a druggable target. Its specialized expression pattern suggests that modulating its activity could have targeted effects with potentially fewer systemic side effects than drugs targeting more ubiquitously expressed channels. In diseases caused by gain-of-function mutations leading to cellular hyperexcitability (e.g., certain epilepsies or cardiac arrhythmias), developing small-molecule inhibitors to block the channel could be a viable therapeutic strategy. Conversely, for loss-of-function channelopathies, small-molecule potentiators or activators could restore proper ion homeostasis. Its potential role in a range of disorders affecting the nervous, renal, and cardiac systems makes it a compelling target for future therapeutic development.

Genular Protein ID: 3742984115

Symbol: TM38A_HUMAN

Name: Transmembrane protein 38A

UniProtKB Accession Codes:

Q9H6F2 A8K9P9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEBI 4 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 4 Ensembl 1 ExpressionAtlas 1 GO 10 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 1 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 1 Rhea 1 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 17611541

Title: TRIC channels are essential for Ca2+ handling in intracellular stores.

PubMed ID: 17611541

DOI: 10.1038/nature05928

PubMed ID: 38556553

Title: Transmembrane proteins with unknown function (TMEMs) as ion channels: electrophysiological properties, structure, and pathophysiological roles.

PubMed ID: 38556553

DOI: 10.1038/s12276-024-01206-1

Sequence Information:

  • Length: 299
  • Mass: 33260
  • Checksum: 40E9D5917F5E3907
  • Sequence:
    • MELLSALSLG ELALSFSRVP LFPVFDLSYF IVSILYLKYE PGAVELSRRH PIASWLCAML 
HCFGSYILAD LLLGEPLIDY FSNNSSILLA SAVWYLIFFC PLDLFYKCVC FLPVKLIFVA 
MKEVVRVRKI AVGIHHAHHH YHHGWFVMIA TGWVKGSGVA LMSNFEQLLR GVWKPETNEI 
LHMSFPTKAS LYGAILFTLQ QTRWLPVSKA SLIFIFTLFM VSCKVFLTAT HSHSSPFDAL 
EGYICPVLFG SACGGDHHHD NHGGSHSGGG PGAQHSAMPA KSKEELSEGS RKKKAKKAD