Stem Cells International

Stem Cells International / 2013 / Article
Special Issue

Stem Cells and Ion Channels

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Research Article | Open Access

Volume 2013 |Article ID 784629 | https://doi.org/10.1155/2013/784629

Leonhard Linta, Marianne Stockmann, Qiong Lin, André Lechel, Christian Proepper, Tobias M. Boeckers, Alexander Kleger, Stefan Liebau, "Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny", Stem Cells International, vol. 2013, Article ID 784629, 25 pages, 2013. https://doi.org/10.1155/2013/784629

Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny

Academic Editor: Michael Levin
Received31 Jan 2013
Accepted06 Mar 2013
Published15 Apr 2013

Abstract

Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated. Additionally, iPSCs express a much higher number of ion channels compared to keratinocytes. Further, to narrow down specificity of ion channel expression in iPS cells we compared their expression patterns with differentiated progeny, namely, neurons and cardiomyocytes derived from iPS cells. To conclude, hiPSCs exhibit a very considerable and diverse ion channel expression pattern. Their detailed analysis could give an insight into their contribution to many cellular processes and even disease mechanisms.

1. Introduction

Ion channels are comprised of a large variety of differing families of pore proteins. Initially, ion channels were mostly known for their role in the nervous system where they play a crucial role in the signal transmission over neurites and synapses. But in fact they are involved in numerous other cellular processes including cell size regulation, muscle contractions, immune system activation [1], or hormone release [2]. Distinct ion channels are furthermore recognized to be of high importance for excitable cells of the heart: cardiomyocytes of the working myocardium as well as cells of the cardiac conduction system. In the heart, specific ion channels are responsible, for example, for the regulated generation of action potentials and for cardiac muscle contraction strength and time [3]. Additionally, ion channels play an important role in several differentiation and maturation processes [46]. The presented study aims to take a closer look at ion channel expression in human-induced pluripotent stem cells (hiPSCs) to give a start point for further analyses of their distinct roles at an early developmental cell state and differentiation processes.

hiPSCs are generated from somatic cells by timed overexpression of specific transcription factors and strongly resemble pluripotent embryonic stem cells [7, 8]. Pluripotency is amongst others defined by the ability to differentiate into cells of all three germ layers and unlimited symmetrical cell division. This cell system is widely utilized for studies investigating developmental processes or disease mechanisms [9, 10]. Although it has become clear that differentiation processes influence ion channel expression [11], the distinct role of ion channels during these processes is so far only poorly understood. Nevertheless, it became evident that certain ion channels play a pivotal role in stem cell biology, including cell fate determination, cell cycle regulation, or cytoskeletal reorganization [6, 1215].

The possibilities of iPSCs include the generation of individual or patient-specific-pluripotent cells, which can be subsequently differentiated into the affected cell types. This is already utilized to study pathomechanisms in a variety of tissues and cell types [9, 1618]. The so-called channelopathies which are based on mutations in ion channels are the cause of developmental disorders and are the subject of various studies [19, 20]. To elucidate the role of ion channels in cell differentiation, maturation or their role in pathomechanisms a well-founded knowledge of ion channel distribution in pluripotent cells, representing one of the earliest stages of development, is indispensable. In that respect, we compared the expression levels of several ion channels in human keratinocytes with their reprogrammed progeny, hiPSCs. Keratinocytes derived from plucked human hair [21, 22] represent one of the most promising cell sources for the generation of the investigated hiPSCs [23]. We have elucidated ion channel regulation for various channel families and their subtypes. Additionally, we compared the expression levels of ion channel families and subtypes, found to be regulated during reprogramming, with iPSC-differentiated progeny, namely, neurons and cardiomyocytes. These comparisons could be a start point to evaluate the contribution and function of different ion channels, for example, for self-renewal and differentiation processes in stem cells.

2. Material and Methods

2.1. Ethical Statement and Donor Information

After informed consent was given by the donors (ethical agreement by the University of Ulm, number 88/12) hair with intact hair roots was gathered by plucking from the scalp after desinfection. We used hair from healthy volunteers (age between 24 to 45 and both male and female gender).

2.2. hiPSC Generation and Cell Culture

Keratinocytes were obtained from plucked human scalp hair as already described [22]. Keratinocytes were propagated in EpiLife medium with HKGS supplement (both Invitrogen, Carlsbad, CA, USA). hiPSCs were generated from keratinocytes by lentiviral transduction of four reprogramming factors (Oct4, Sox2, Klf4, and cMyc) as described earlier [23]. After the reprogramming on rat embryonic fibroblasts they were maintained feeder-free on Matrigel (BD Biosciences, Franklin Lakes, NJ, USA) coated dishes in mTeSR1 medium (Stemcell Technologies, Vancouver, CA, USA).

2.3. Gene Expression Microarrays

Gene expression microarrays were performed for 6 keratinocyte samples and 9 hiPSC samples with the Agilent Whole Human Genome Microarray Kit (4x44k microarray kit G4112F, Agilent Technologies, Santa Clara, CA, USA). 500 ng of total RNA was used to produce Cy3-CTP-labeled cRNA with the Agilent Low RNA Input Liner Amplification Kit. The cRNA was purified and 1,65 μg per array was hybridized for 17 h at 65°C and 10 r.p.m. Afterwards, the arrays were washed with Agilent Gene Expression Wash Buffers one and two and finally with acetonitrile for 1 min. The slides were scanned using Scan Control 7.0 software with a resolution of 5 μm. Scan data was extracted with the Feature Extraction 9.1 software. Expression levels were background adjusted and quantile normalized with the GeneSpring GX 12 software. Differential expression between keratinocytes and hiPSCs was analyzed using student’s t-test. A fold change > 2 and a value < 0.05 was considered significant and highlighted bold (upregulation) or italic (downregulation) in the results table. For comparisons of iPSCs with iPSC-derived neurons published data from GSE34879 (GSM856936, GSM856937, GSM856915, GSM856916) and for cardiomyocytes GSE17579 (GSM438022, GSM438026, GSM438034, GSM438021, GSM438032, GSM438036) were used (both from NCBI Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo/). Fold change is shown if >2.

3. Results

3.1. Differential Expression of Ion Channels in hiPSCs Compared to Keratinocytes

We first compared the expression of various ion channel families from keratinocytes to hiPSCs and from hiPSCs to cardiomyocytes and neurons, respectively. From the 387 probes (Table 1) binding in ion channel genes from parental keratinocytes to hiPSCs, 101 (26%) showed a significant increase in expression (fold change > 2, ; labeled in bold) while 23 (6%) showed a significant decrease (fold change > −2, ; labeled in italic). In a second step differentially regulated ion channels from hiPSCs to hiPSC-derived neurons were investigated and we found 29 ion channel transcripts to be upregulated (fold change > 2; labeled in bold) while 6 showed a significant decrease (fold change > −2; labeled in italic). For cardiomyocytes, mRNA levels of only 7 ion channel members were upregulated (fold change > 2; labeled in bold) and 10 mRNA levels showed a significant decrease (fold change > −2; labeled in italic).

(a) Voltage-gated calcium channels

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Calcium channel, voltage-dependent, P/Q type, alpha 1A subunit, transcript variant 1NM_000068CACNA1A −1.32
Calcium channel, voltage-dependent, N type, alpha 1B subunitNM_000718CACNA1B −1.10
Calcium channel, voltage-dependent, N type, alpha 1B subunit [Source: HGNC Symbol; Acc: 1389]ENST00000277550CACNA1B −1.14
Calcium channel, voltage-dependent, N type, alpha 1B subunitNM_000718CACNA1B 6.82
Calcium channel, voltage-dependent, N type, alpha 1B subunit [Source: HGNC Symbol; Acc: 1389]ENST00000277551CACNA1B −1.57
Calcium channel, voltage-dependent, L type, alpha 1C subunit, transcript variant 18NM_000719CACNA1C −1.37
Calcium channel, voltage-dependent, L type, alpha 1C subunit, transcript variant 18NM_000719CACNA1C 2.372.94
Calcium channel, voltage-dependent, L type, alpha 1D subunit, transcript variant 1NM_000720CACNA1D 1.58
Calcium channel, voltage-dependent, R type, alpha 1E subunit, transcript variant 3NM_000721CACNA1E3.10 02 −4.48 2.08
Calcium channel, voltage-dependent, R type, alpha 1E subunit [Source: HGNC Symbol; Acc: 1392]ENST00000524607CACNA1E 1.05
Calcium channel, voltage-dependent, L type, alpha 1F subunitNM_005183CACNA1F 1.02
Calcium channel, voltage-dependent, T type, alpha 1G subunit, transcript variant 15NM_198397CACNA1G −1.124.60
Calcium channel, voltage-dependent, T type, alpha 1G subunit, transcript variant 1NM_018896CACNA1G 6.96
Calcium channel, voltage-dependent, T type, alpha 1H subunit, transcript variant 1NM_021098CACNA1H 6.78
Calcium channel, voltage-dependent, T type, alpha 1I subunit, transcript variant 1NM_021096CACNA1I 37.25
Calcium channel, voltage-dependent, T type, alpha 1I subunit, transcript variant 1NM_021096CACNA1I −1.56
Calcium channel, voltage-dependent, L type, alpha 1S subunitNM_000069CACNA1S −1.97
Calcium channel, voltage-dependent, alpha 2/delta subunit 1NM_000722CACNA2D1 9.65
Calcium channel, voltage-dependent, alpha 2/delta subunit 2, transcript variant 1NM_001005505CACNA2D2 62.502.02
Calcium channel, voltage-dependent, alpha 2/delta subunit 3NM_018398CACNA2D3 5.422.55
Calcium channel, voltage-dependent, alpha 2/delta subunit 3AF516696CACNA2D3 33.67
Calcium channel, voltage-dependent, alpha 2/delta subunit 4NM_172364CACNA2D4 −1.41
Calcium channel, voltage-dependent, beta 1 subunit, transcript variant 3NM_199248CACNB1 −1.14
Calcium channel, voltage-dependent, beta 1 subunit, transcript variant 1NM_000723CACNB1 −1.02
Calcium channel, voltage-dependent, beta 1 subunit, transcript variant 1NM_000723CACNB1 1.04
cDNA FLJ45229 fis, clone BRCAN2020972, AK128769CACNB2 1.02
Calcium channel, voltage-dependent, beta 2 subunit, transcript variant 1NM_000724CACNB2 3.45
Calcium channel, voltage-dependent, beta 3 subunit, transcript variant 1NM_000725CACNB3 −1.939.56
Calcium channel, voltage-dependent, beta 3 subunit, transcript variant 1NM_000725CACNB3 1.09
Calcium channel, voltage-dependent, beta 4 subunit, transcript variant 1NM_001005747CACNB4 4.43
Calcium channel, voltage-dependent, gamma subunit 1NM_000727CACNG1 1.02
Calcium channel, voltage-dependent, gamma subunit 2NM_006078CACNG2 −1.29
Calcium channel, voltage-dependent, gamma subunit 2NM_006078CACNG2 1.09
Calcium channel, voltage-dependent, gamma subunit 3NM_006539CACNG3 −1.95
Calcium channel, voltage-dependent, gamma subunit 4NM_014405CACNG4 1.14
Calcium channel, voltage-dependent, gamma subunit 5NM_145811CACNG5 −1.13
Calcium channel, voltage-dependent, gamma subunit 5 [Source: HGNC Symbol; Acc: 1409]ENST00000169565CACNG5 −1.56
Calcium channel, voltage-dependent, gamma subunit 6, transcript variant 1NM_145814CACNG6 46.40
Calcium channel, voltage-dependent, gamma subunit 7NM_031896CACNG7 1439.363.37
Calcium channel, voltage-dependent, gamma subunit 7NM_031896CACNG7 1.26
Calcium channel, voltage-dependent, gamma subunit 8NM_031895CACNG8 1.43
Calcium channel, voltage-dependent, gamma subunit 8NM_031895CACNG8 9.70

(b) Sperm-associated cation channels

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Cation channel, sperm associated 1NM_053054CATSPER1 1.51
Cation channel, sperm associated 2, transcript variant 2NM_172095CATSPER21.32 04 −2.78
Cation channel, sperm associated 2, transcript variant 4NM_172097CATSPER2 −1.78
Cation channel, sperm associated 3NM_178019CATSPER3 1.93
Cation channel, sperm associated 4NM_198137CATSPER4 1.48
Cation channel, sperm-associated, betaNM_024764CATSPERB −1.25
Cation channel, sperm-associated, gammaNM_021185CATSPERG 1.34

(c) Nicotinic acetylcholine receptors

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Cholinergic receptor, nicotinic, alpha 1 (muscle), transcript variant 1NM_001039523CHRNA1 −1.10
Cholinergic receptor, nicotinic, alpha 1 (muscle), (cDNA clone IMAGE: 4124038), with apparent retained intronBC006314CHRNA1 1.47
Cholinergic receptor, nicotinic, alpha 2 (neuronal)NM_000742CHRNA2 −1.30
Cholinergic receptor, nicotinic, alpha 3, transcript variant 1NM_000743CHRNA3 34.22
Cholinergic receptor, nicotinic, alpha 4NM_000744CHRNA4 1.15
Cholinergic receptor, nicotinic, alpha 4 (neuronal), exon 1X89741CHRNA42.79 02 −2.53
Cholinergic receptor, nicotinic, alpha 5NM_000745CHRNA5 3.41
Cholinergic receptor, nicotinic, alpha 6, transcript variant 1NM_004198CHRNA6 −1.272.21
Cholinergic receptor, nicotinic, alpha 7, transcript variant 1NM_000746CHRNA7 1.86
Cholinergic receptor, nicotinic, alpha 7, transcript variant 2NM_001190455CHRNA7 13.24
Cholinergic receptor, nicotinic, alpha 9NM_017581CHRNA9 6.15
Cholinergic receptor, nicotinic, alpha 10NM_020402CHRNA10 1.57
Cholinergic receptor, nicotinic, beta 1 (muscle)NM_000747CHRNB18.07 04 −2.47
Cholinergic receptor, nicotinic, beta 1 (muscle)NM_000747CHRNB1 −1.92
Cholinergic receptor, nicotinic, beta 2 (neuronal)NM_000748CHRNB26.03 04 −3.01
Cholinergic receptor, nicotinic, beta 2 (neuronal) [Source: HGNC Symbol; Acc: 1962]ENST00000368476CHRNB2 32.05
Cholinergic receptor, nicotinic, beta 3NM_000749CHRNB3 1.12
Cholinergic receptor, nicotinic, beta 4NM_000750CHRNB4 4.20
Cholinergic receptor, nicotinic, deltaNM_000751CHRND 1.01
Cholinergic receptor, nicotinic, epsilonNM_000080CHRNE −1.20
Cholinergic receptor, nicotinic, gammaNM_005199CHRNG 1.14

(d) Cyclic nucleotide-gated channels

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Cyclic nucleotide-gated channel alpha 1, transcript variant 2NM_000087CNGA1
Cyclic nucleotide-gated channel alpha 1, transcript variant 2NM_000087CNGA1
Cyclic nucleotide-gated channel alpha 3, transcript variant 1NM_001298CNGA3
Cyclic nucleotide-gated channel alpha 4NM_001037329CNGA4
Cyclic nucleotide-gated channel beta 1, transcript variant 1NM_001297CNGB19.22 03 −2.05
Cyclic nucleotide-gated channel beta 1, transcript variant 1NM_001297CNGB1
Cyclic nucleotide-gated channel beta 3NM_019098CNGB3

(e) GABA receptors

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Gamma-aminobutyric acid (GABA) A receptor, alpha 1, transcript variant 1NM_000806GABRA1 1.41
Gamma-aminobutyric acid (GABA) A receptor, alpha 1, transcript variant 1NM_000806GABRA1 1.05
Gamma-aminobutyric acid (GABA) A receptor, alpha 2, transcript variant 1NM_000807GABRA2 1.70
Gamma-aminobutyric acid (GABA) A receptor, alpha 2, transcript variant 1NM_000807GABRA2 1.48
Gamma-aminobutyric acid (GABA) A receptor, alpha 3NM_000808GABRA3 1.43
Gamma-aminobutyric acid (GABA) A receptor, alpha 4, transcript variant 1NM_000809GABRA4 1.43
Gamma-aminobutyric acid (GABA) A receptor, alpha 4, transcript variant 1NM_000809GABRA4 1.05
Gamma-aminobutyric acid (GABA) A receptor, alpha 5, transcript variant 1NM_000810GABRA5 14.41
Gamma-aminobutyric acid (GABA) A receptor, alpha 6NM_000811GABRA6 1.23
Gamma-aminobutyric acid (GABA) A receptor, beta 1NM_000812GABRB1 1.43
Gamma-aminobutyric acid (GABA) A receptor, beta 2, transcript variant 2NM_000813GABRB2 1.94
Gamma-aminobutyric acid (GABA) A receptor, beta 3, transcript variant 1NM_000814GABRB3 85.93−4.49
Gamma-aminobutyric acid (GABA) A receptor, beta 3, transcript variant 1NM_000814GABRB3 115.69
Gamma-aminobutyric acid (GABA) A receptor, deltaNM_000815GABRD 3.02
Gamma-aminobutyric acid (GABA) A receptor, epsilonNM_004961GABRE5.83 05 −5.47
Gamma-aminobutyric acid (GABA) A receptor, Gamma 1NM_173536GABRG1 1.24
Gamma-aminobutyric acid (GABA) A receptor, Gamma 1NM_173536GABRG1 2.19
Gamma-aminobutyric acid (GABA) A receptor, Gamma 2, transcript variant 1NM_198904GABRG2 1.14
Gamma-aminobutyric acid (GABA) A receptor, Gamma 2, transcript variant 2NM_000816GABRG2 1.72
Gamma-aminobutyric acid (GABA) A receptor, Gamma 2, transcript variant 2NM_000816GABRG2 8.41
Gamma-aminobutyric acid (GABA) A receptor, Gamma 3NM_033223GABRG3 2.00
Gamma-aminobutyric acid (GABA) A receptor, Gamma 3NM_033223GABRG3 1.61
Gamma-aminobutyric acid (GABA) A receptor, piNM_014211GABRP −1.1217.25
Gamma-aminobutyric acid (GABA) receptor, thetaNM_018558GABRQ 1.56
Gamma-aminobutyric acid (GABA) receptor, thetaNM_018558GABRQ −1.27
Gamma-aminobutyric acid (GABA) receptor, theta [Source: HGNC Symbol; Acc: 14454]ENST00000370306GABRQ 52.17
Gamma-aminobutyric acid (GABA) receptor, rho 1NM_002042GABRR1 −1.04
Gamma-aminobutyric acid (GABA) receptor, rho 2NM_002043GABRR2 1.54
Gamma-aminobutyric acid (GABA) receptor, rho 3NM_001105580GABRR3 −1.34

(f) Glycine receptors

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Glycine receptor, alpha 1, transcript variant 2NM_000171GLRA1 −1.29
Glycine receptor, alpha 2, transcript variant 1NM_002063GLRA2 1.4211.41
Glycine receptor, alpha 3, transcript variant 1NM_006529GLRA3 −1.26
Glycine receptor, alpha 3 [Source: HGNC Symbol; Acc: 4328]ENST00000274093GLRA3 1.64
Glycine receptor, alpha 3, transcript variant 1NM_006529GLRA3 1.41
Glycine receptor, alpha 4, transcript variant 1NM_001024452GLRA4 1.17
Glycine receptor, beta, transcript variant 1NM_000824GLRB −1.696.61

(g) Ionotropic glutamate receptors

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Glutamate receptor, ionotropic, AMPA 1, transcript variant 1NM_000827GRIA1 −1.202.06
Glutamate receptor, ionotropic, AMPA 2, transcript variant 1NM_000826GRIA2 −1.8721.26
Glutamate receptor, ionotropic, AMPA 2, transcript variant 1NM_000826GRIA2 1.33
Glutamate receptor, ionotropic, AMPA 2, transcript variant 1NM_000826GRIA2 1.22
Glutamate receptor, ionotropic, AMPA 3, transcript variant 2NM_000828GRIA3 1.26
Glutamate receptor, ionotropic, AMPA 3 [Source: HGNC Symbol; Acc: 4573]ENST00000371264GRIA3 1.50
Glutamate receptor, ionotropic, AMPA 3, transcript variant 2NM_000828GRIA3 −1.05
Glutamate receptor, ionotropic, AMPA 4, transcript variant 1NM_000829GRIA4 1.803.73
Glutamate receptor, ionotropic, delta 1NM_017551GRID1 1.50
Glutamate receptor, ionotropic, delta 1NM_017551GRID1 3.63
Glutamate receptor, ionotropic, delta 2NM_001510GRID2 −1.11
Glutamate receptor, ionotropic, delta 2NM_001510GRID2 55.66
Glutamate receptor, ionotropic, kainate 1, transcript variant 1NM_000830GRIK1 1.292.58
Glutamate receptor, ionotropic, kainate 2, transcript variant 3NM_001166247GRIK2 1.562.53
Glutamate receptor, ionotropic, kainate 2, transcript variant 1NM_021956GRIK2 −2.01
Glutamate receptor, ionotropic, kainate 2, transcript variant 2NM_175768GRIK2 1.08
Glutamate receptor, ionotropic, kainate 3NM_000831GRIK3 1.64
Glutamate receptor, ionotropic, kainate 3NM_000831GRIK3 22.64
Glutamate receptor, ionotropic, kainate 4 [Source: HGNC Symbol; Acc: 4582]ENST00000527524GRIK4 18.10
Glutamate receptor, ionotropic, kainate 4NM_014619GRIK4 2.54
Glutamate receptor, ionotropic, kainate 5NM_002088GRIK5 1.79−2.41
Glutamate receptor, ionotropic, N-methyl D-aspartate 1, transcript variant NR1-3NM_007327GRIN11.93 02 −3.02 2.69
Glutamate receptor, ionotropic, N-methyl D-aspartate 1, transcript variant NR1-3NM_007327GRIN1 −2.45
Glutamate receptor, ionotropic, N-methyl D-aspartate 1, transcript variant NR1-3NM_007327GRIN1 −1.65
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 2NM_000833GRIN2A 1.18
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 2NM_000833GRIN2A −1.02
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 1NM_001134407GRIN2A 29.85
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 2NM_000833GRIN2A 1.55
Glutamate receptor, ionotropic, N-methyl D-aspartate 2BNM_000834GRIN2B −1.26
Glutamate receptor, ionotropic, N-methyl D-aspartate 2CNM_000835GRIN2C −1.08
Glutamate receptor, ionotropic, N-methyl D-aspartate 2CNM_000835GRIN2C 1.13
Glutamate receptor, ionotropic, N-methyl D-aspartate 2DNM_000836GRIN2D −1.82
Glutamate receptor, ionotropic, N-methyl-D-aspartate 3ANM_133445GRIN3A −1.41
Glutamate receptor, ionotropic, N-methyl-D-aspartate 3BNM_138690GRIN3B −1.02
Glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (glutamate binding), transcript variant 1NM_000837GRINA3.68 04 −2.05 2.05
NMDA receptor glutamate-binding chain (hnrgw), partialU44954GRINA −1.81

(h) Hyperpolarization-activated cyclic nucleotide-gated channels

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1NM_021072HCN1 52.85
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1NM_021072HCN1 9.91
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 2NM_001194HCN2 −1.63
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 3NM_020897HCN3 2.126.56
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 4NM_005477HCN4 −1.66

(i) Serotonin receptors

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

5-hydroxytryptamine (serotonin) receptor 3A, transcript variant 1NM_213621HTR3A 2.77−2.20
5-hydroxytryptamine (serotonin) receptor 3A, transcript variant 1NM_213621HTR3A 11.11
5-hydroxytryptamine (serotonin) receptor 3BNM_006028HTR3B −1.54
5-hydroxytryptamine (serotonin) receptor 3, family member CNM_130770HTR3C 1.34
5-hydroxytryptamine (serotonin) receptor 3 family member D, transcript variant 2NM_182537HTR3D −1.37
5-hydroxytryptamine (serotonin) receptor 3, family member ENM_182589HTR3E −1.44

(j) Voltage-gated potassium channels

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Potassium voltage-gated channel, shaker-related subfamily, member 1 (episodic ataxia with myokymia)NM_000217KCNA1 2.00
Potassium voltage-gated channel, shaker-related subfamily, member 1 (episodic ataxia with myokymia)NM_000217KCNA1 1.87
Potassium voltage-gated channel, shaker-related subfamily, member 2, transcript variant 2NM_001204269KCNA2 1.33
Potassium voltage-gated channel, shaker-related subfamily, member 2, transcript variant 1NM_004974KCNA2 1.06
Potassium voltage-gated channel, shaker-related subfamily, member 3NM_002232KCNA3 1.76
Potassium voltage-gated channel, shaker-related subfamily, member 4NM_002233KCNA4 1.11
Potassium voltage-gated channel, shaker-related subfamily, member 5NM_002234KCNA5 4.115.63
Potassium voltage-gated channel, shaker-related subfamily, member 6NM_002235KCNA6 2.28
Potassium voltage-gated channel, shaker-related subfamily, member 7NM_031886KCNA7 3.67
Potassium voltage-gated channel, shaker-related subfamily, member 7NM_031886KCNA7 2.39
Potassium voltage-gated channel, shaker-related subfamily, member 10NM_005549KCNA10 −1.62
Potassium voltage-gated channel, shaker-related subfamily, beta member 1, transcript variant 2NM_003471KCNAB1 1.46
Potassium voltage-gated channel, shaker-related subfamily, beta member 1, transcript variant 2NM_003471KCNAB1 2.42
Potassium voltage-gated channel, shaker-related subfamily, beta member 1, transcript variant 2NM_003471KCNAB1 3.06
Potassium voltage-gated channel, shaker-related subfamily, beta member 2, transcript variant 1NM_003636KCNAB2 −1.35
Potassium voltage-gated channel, shaker-related subfamily, beta member 2, transcript variant 1NM_003636KCNAB2 1.26
Potassium voltage-gated channel, shaker-related subfamily, beta member 3 [Source: HGNC Symbol; Acc: 6230]ENST00000303790KCNAB3 1.62
Potassium voltage-gated channel, shaker-related subfamily, beta member 3NM_004732KCNAB3 1.35
Potassium voltage-gated channel, Shab-related subfamily, member 1NM_004975KCNB1 16.322.59
Potassium voltage-gated channel, Shab-related subfamily, member 2NM_004770KCNB2 4.58
Potassium voltage-gated channel, Shaw-related subfamily, member 1, transcript variant ANM_001112741KCNC1 1.75
Potassium voltage-gated channel, Shaw-related subfamily, member 1, transcript variant BNM_004976KCNC1 13.97
Potassium voltage-gated channel, Shaw-related subfamily, member 1, transcript variant ANM_001112741KCNC1 1.56
Potassium voltage-gated channel, Shaw-related subfamily, member 2, transcript variant 1NM_139136KCNC2 1.06
Potassium voltage-gated channel, Shaw-related subfamily, member 2, transcript variant 2NM_139137KCNC2 1.34
Potassium voltage-gated channel, Shaw-related subfamily, member 3NM_004977KCNC3 1.20
Potassium voltage-gated channel, Shaw-related subfamily, member 4, transcript variant 3NM_001039574KCNC4 −1.40
Potassium voltage-gated channel, Shal-related subfamily, member 1NM_004979KCND1 7.11
Potassium voltage-gated channel, Shal-related subfamily, member 2NM_012281KCND2 91.082.76−2.57
Potassium voltage-gated channel, Shal-related subfamily, member 2NM_012281KCND2 21.83
Potassium voltage-gated channel, Shal-related subfamily, member 3 [Source: HGNC Symbol; Acc: 6239]ENST00000369697KCND3 −1.36
Potassium voltage-gated channel, Shal-related subfamily, member 3, transcript variant 1NM_004980KCND3 1.55
Potassium voltage-gated channel, Shal-related subfamily, member 3, transcript variant 1NM_004980KCND3 1.37
Potassium voltage-gated channel, Shal-related subfamily, member 3 [Source: HGNC Symbol; Acc: 6239]ENST00000369697KCND3 −1.84
Potassium voltage-gated channel, Isk-related family, member 1, transcript variant 2NM_000219KCNE1 −1.45
Potassium voltage-gated channel, Isk-related family, member 1, transcript variant 2NM_000219KCNE1 1.25
KCNE1-likeNM_012282KCNE1L 4.44−2.18
KCNE1-likeNM_012282KCNE1L 3.65
KCNE1-likeNM_012282KCNE1L 1.88
Potassium voltage-gated channel, Isk-related family, member 2NM_172201KCNE2 3.93
Potassium voltage-gated channel, Isk-related family, member 3NM_005472KCNE3 52.36
Potassium voltage-gated channel, Isk-related family, member 4NM_080671KCNE4 1.20
Potassium voltage-gated channel, subfamily F, member 1NM_002236KCNF1 6.482.84
Potassium voltage-gated channel, subfamily G, member 1NM_002237KCNG1 −1.82
Potassium voltage-gated channel, subfamily G, member 1NM_002237KCNG1 −1.65
Potassium voltage-gated channel, subfamily G, member 2NM_012283KCNG2 1.32
Potassium voltage-gated channel, subfamily G, member 3, transcript variant 1NM_133329KCNG3 58.95−2.93
Potassium voltage-gated channel, subfamily G, member 4NM_172347KCNG43.36 03 −3.33
Potassium voltage-gated channel, subfamily G, member 4, (cDNA clone IMAGE: 3028985)BC008969KCNG42.24 04 −3.29
Potassium voltage-gated channel, subfamily H (eag-related), member 1, transcript variant 1NM_172362KCNH1 −1.15
Potassium voltage-gated channel, subfamily H (eag-related), member 2, transcript variant 1NM_000238KCNH2 37.53
Potassium voltage-gated channel, subfamily H (eag-related), member 2, transcript variant 2NM_172056KCNH2 1.73
Potassium voltage-gated channel, subfamily H (eag-related), member 3NM_012284KCNH3 1.01
Potassium voltage-gated channel, subfamily H (eag-related), member 4NM_012285KCNH4 −1.24
Potassium voltage-gated channel, subfamily H (eag-related), member 5, transcript variant 2NM_172376KCNH5 2.96
Potassium voltage-gated channel, subfamily H (eag-related), member 5, transcript variant 1NM_139318KCNH5 1.47
Potassium voltage-gated channel, subfamily H (eag-related), member 6, transcript variant 2NM_173092KCNH6 3.04
cDNA FLJ33650 fis, clone BRAMY2024514, highly similar to Rattus norvegicus Potassium channel (erg2)AK090969KCNH6 12.42
Potassium voltage-gated channel, subfamily H (eag-related), member 6, transcript variant 2NM_173092KCNH6 2.29
Potassium voltage-gated channel, subfamily H (eag-related), member 7, transcript variant 2NM_173162KCNH7 −1.40
Potassium voltage-gated channel, subfamily H (eag-related), member 7, transcript variant 1NM_033272KCNH7 −1.09
Potassium voltage-gated channel, subfamily H (eag-related), member 8NM_144633KCNH8 24.572.97
Kv channel interacting protein 1, transcript variant 1NM_001034837KCNIP1 1.964.24
Kv channel interacting protein 2, transcript variant 7NM_173197KCNIP2 1.21
Kv channel interacting protein 2, transcript variant 1NM_014591KCNIP2 1.96
Kv channel interacting protein 3, calsenilin, transcript variant 1NM_013434KCNIP31.15 03 −3.47
Kv channel interacting protein 4, transcript variant 5NM_001035003KCNIP4 1.162.01
Kv channel interacting protein 4, transcript variant 5NM_001035003KCNIP4 1.05
Potassium voltage-gated channel, KQT-like subfamily, member 1, transcript variant 1NM_000218KCNQ1 79.52
Potassium voltage-gated channel, KQT-like subfamily, member 2, transcript variant 5NM_172109KCNQ2 3408.43
Potassium voltage-gated channel, KQT-like subfamily, member 2, transcript variant 3NM_004518KCNQ2 1.82
Potassium voltage-gated channel, KQT-like subfamily, member 2, (cDNA clone IMAGE: 4154700)BC020384KCNQ2 37.12
Potassium voltage-gated channel, KQT-like subfamily, member 3, transcript variant 1NM_004519KCNQ3 −1.69
Potassium voltage-gated channel, KQT-like subfamily, member 4, transcript variant 1NM_004700KCNQ4 1.02
Potassium voltage-gated channel, KQT-like subfamily, member 5, transcript variant 1NM_019842KCNQ5 −1.79
Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 1NM_002251KCNS1 −1.27−2.64
Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 2NM_020697KCNS2 −2.452.11
Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 3NM_002252KCNS3 2.22−2.61 −2.39
Potassium channel, subfamily T, member 1 (sodium activated)NM_020822KCNT1 −2.17
Potassium channel, subfamily V, member 1NM_014379KCNV1 1.58
Potassium channel, subfamily V, member 2NM_133497KCNV2 −1.16

(k) Inwardly rectifying potassium channels

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Potassium inwardly-rectifying channel, subfamily J, member 1, transcript variant rom-k5NM_153767KCNJ1 2.66
Potassium inwardly-rectifying channel, subfamily J, member 1, transcript variant rom-k5NM_153767KCNJ1 −1.05
Potassium inwardly-rectifying channel, subfamily J, member 2NM_000891KCNJ2 4.38
Potassium inwardly-rectifying channel, subfamily J, member 3NM_002239KCNJ3 1.34
Potassium inwardly-rectifying channel, subfamily J, member 4, transcript variant 1NM_152868KCNJ4 2.30
Potassium inwardly-rectifying channel, subfamily J, member 5NM_000890KCNJ51.88 08 −45.40
Potassium inwardly-rectifying channel, subfamily J, member 5NM_000890KCNJ54.42 12 −109.11
Potassium inwardly-rectifying channel, subfamily J, member 6NM_002240KCNJ6 6.755.54
Potassium inwardly-rectifying channel, subfamily J, member 8NM_004982KCNJ8 5.972.74
Potassium inwardly-rectifying channel, subfamily J, member 9 [Source: HGNC Symbol; Acc: 6270]ENST00000368088KCNJ9 1.49
Potassium inwardly-rectifying channel, subfamily J, member 9NM_004983KCNJ9 1.79
Potassium inwardly-rectifying channel, subfamily J, member 10NM_002241KCNJ10 4.14
Potassium inwardly-rectifying channel, subfamily J, member 10NM_002241KCNJ10 1.01
Potassium inwardly-rectifying channel, subfamily J, member 11, transcript variant 1NM_000525KCNJ11 2.93
Potassium inwardly-rectifying channel, subfamily J, member 12NM_021012KCNJ12 1.47
Potassium inwardly-rectifying channel, subfamily J, member 12NM_021012KCNJ12 5.81
Potassium inwardly-rectifying channel, subfamily J, member 13, transcript variant 1NM_002242KCNJ13 1.20
Potassium inwardly-rectifying channel, subfamily J, member 14, transcript variant 2NM_170720KCNJ14 −1.40
Potassium inwardly-rectifying channel, subfamily J, member 15, transcript variant 1NM_170736KCNJ153.41 08 −150.95
Potassium inwardly-rectifying channel, subfamily J, member 16, transcript variant 2NM_170741KCNJ16 −1.93

(l) Two-P potassium channels

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Potassium channel, subfamily K, member 1NM_002245KCNK1 −1.68
Potassium channel, subfamily K, member 2, transcript variant 1NM_001017424KCNK2 1.57
Potassium channel, subfamily K, member 3NM_002246KCNK3 1.002.36
Potassium channel, subfamily K, member 3NM_002246KCNK3 −1.10
Potassium channel, subfamily K, member 3NM_002246KCNK3 −1.30
Potassium channel, subfamily K, member 3 [Source: HGNC Symbol; Acc: 6278]ENST00000302909KCNK3 1.52
Potassium channel, subfamily K, member 4NM_033310KCNK4 −1.142.05
Potassium channel, subfamily K, member 5NM_003740KCNK5 29.46−2.35 −2.03
Potassium channel, subfamily K, member 6NM_004823KCNK61.22 06 −3.48 −2.20
Potassium channel, subfamily K, member 6NM_004823KCNK62.05 08 −5.11
Potassium channel, subfamily K, member 6NM_004823KCNK67.04E−06 −5.22
Potassium channel, subfamily K, member 7, transcript variant ANM_033347KCNK7 −1.52
Potassium channel, subfamily K, member 9NM_016601KCNK9 −1.29
Potassium channel, subfamily K, member 10, transcript variant 1NM_021161KCNK10 −1.30
Potassium channel, subfamily K, member 10, transcript variant 2NM_138317KCNK10 1.43
Potassium channel, subfamily K, member 12NM_022055KCNK12 23.40−5.58
Potassium channel, subfamily K, member 13NM_022054KCNK13 −1.10
Potassium channel, subfamily K, member 15NM_022358KCNK15 −1.50
Potassium channel, subfamily K, member 15NM_022358KCNK15 −1.09
Pancreatic potassium channel TALK-1d; alternatively splicedAY253147KCNK162.17 02 −2.43
Potassium channel, subfamily K, member 17, transcript variant 1NM_031460KCNK17 28.60
Potassium channel, subfamily K, member 17, transcript variant 1NM_031460KCNK17 19.62
Potassium channel, subfamily K, member 18NM_181840KCNK18 1.61

(m) Calcium-activated potassium channels

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2NM_002247KCNMA1 1.842.01
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 1NM_001014797KCNMA1 1.32
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2NM_002247KCNMA1 2.27
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2NM_002247KCNMA1 1.44
Maxi-K channel HSLOAF349445KCNMA1 1.44
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2NM_002247KCNMA1 −1.23
Potassium large conductance calcium-activated channel, subfamily M, beta member 1NM_004137KCNMB1 −1.41
Potassium large conductance calcium-activated channel, subfamily M, beta member 1NM_004137KCNMB1 7.82
Potassium large conductance calcium-activated channel, subfamily M, beta member 2, transcript variant 1NM_181361KCNMB2 1.56
Potassium large conductance calcium-activated channel, subfamily M, beta member 2, transcript variant 1NM_181361KCNMB2 1.47
Potassium large conductance calcium-activated channel, subfamily M beta member 3, transcript variant 1NM_171828KCNMB3 2.63
Potassium large conductance calcium-activated channel, subfamily M, beta member 4NM_014505KCNMB4 103.99
Potassium large conductance calcium-activated channel, subfamily M, beta member 4 [Source: HGNC Symbol; Acc: 6289]ENST00000258111KCNMB4 18.40
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 1NM_002248KCNN1 4.67
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2, transcript variant 1NM_021614KCNN2 22.23−3.63
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3, transcript variant 1NM_002249KCNN3 8.25
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3, transcript variant 3NM_001204087KCNN3 15.29
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4NM_002250KCNN4 −1.84

(n) P2X receptors

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Purinergic receptor P2X, ligand-gated ion channel, 1NM_002558P2RX1 1.14
Purinergic receptor P2X, ligand-gated ion channel, 2, transcript variant 4NM_170683P2RX2 −1.66
Purinergic receptor P2X, ligand-gated ion channel, 3NM_002559P2RX3 −1.76
Purinergic receptor P2X, ligand-gated ion channel, 4NM_002560P2RX4 −1.03
Purinergic receptor P2X, ligand-gated ion channel, 5, transcript variant 1NM_002561P2RX5 6.97
Purinergic receptor P2X, ligand-gated ion channel, 5, transcript variant 2NM_175080P2RX5 1.54
Purinergic receptor P2X, ligand-gated ion channel, 6 [Source: HGNC Symbol; Acc: 8538]ENST00000413302P2RX6 1.68
Purinergic receptor P2X, ligand-gated ion channel, 7, transcript variant 1NM_002562P2RX7 1.23
Purinergic receptor P2X, ligand-gated ion channel, 7, transcript variant 1NM_002562P2RX7 1.04

(o) Transient receptor potential channels

Gene nameAccession numberGene symbol Fold change
Ker → hiPSC
Fold change
hiPSC → Neuron
Fold change hiPSC → CM

Polycystic kidney disease 2 (autosomal dominant)NM_000297PKD2 1.79
Polycystic kidney disease 2 (autosomal dominant)NM_000297PKD2 1.98
Polycystic kidney disease 2-like 1NM_016112PKD2L1 4.66
Polycystic kidney disease 2-like 2NM_014386PKD2L2 1.49
Polycystic kidney disease 2-like 2NM_014386PKD2L2 1.19
Polycystic kidney disease 2-like 2NM_014386PKD2L2 1.09
Transient receptor potential cation channel, subfamily A, member 1NM_007332TRPA1 1.74
Transient receptor potential cation channel, subfamily A, member 1NM_007332TRPA1 2.70
Transient receptor potential cation channel, subfamily C, member 1NM_003304TRPC1 2.01
Transient receptor potential cation channel, subfamily C, member 3, transcript variant 2NM_003305TRPC3