Descriptions
Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels contribute to electrical activity in neurons and cardiomyocytes. HCN1-4 share a similar multidomain organization with an N-terminal transmembrane region, a C-terminal intracellular region (IR) and a cyclic nucleotide-binding domain (CBD). Channel opening is primarily stimulated by transmembrane elements that sense membrane hyperpolarization. In the absence of cAMP, the CBD shows steric clashes with the C-linker within IR, which become energetically unfavored. The steric clashes are eliminated by cAMP binding, which selects for a CBD state devoid of steric clashes with the tetrameric C-linker and facilitates channel opening.
Autoinhibitory domains (AIDs)
Target domain |
263-522 (Ion transport domain) |
Relief mechanism |
Ligand binding |
Assay |
|
Target domain |
263-522 (Ion transport domain) |
Relief mechanism |
Ligand binding |
Assay |
|
Accessory elements
No accessory elements
References
- Akimoto M et al. (2014) "A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP", The Journal of biological chemistry, 289, 22205-20
- Xu X et al. (2010) "Structural basis for the cAMP-dependent gating in the human HCN4 channel", The Journal of biological chemistry, 285, 37082-91
- Yeon JH et al. (2016) "Systems-wide Identification of cis-Regulatory Elements in Proteins", Cell systems, 2, 89-100
- Wicks NL et al. (2011) "Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating", Proceedings of the National Academy of Sciences of the United States of America, 108, 609-14
Autoinhibited structure
Activated structure
1 structures for O70507
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| AF-O70507-F1 | Predicted | AlphaFoldDB |
No variants for O70507
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| No variants for O70507 | |||||
No associated diseases with O70507
8 regional properties for O70507
| Type | Name | Position | InterPro Accession |
|---|---|---|---|
| domain | SH3 domain | 156 - 215 | IPR001452-1 |
| domain | SH3 domain | 226 - 285 | IPR001452-2 |
| domain | Phox homology | 4 - 125 | IPR001683 |
| domain | Neutrophil cytosol factor 1, C-terminal | 358 - 390 | IPR015039 |
| domain | Neutrophil cytosol factor 1, PBR/AIR | 282 - 330 | IPR032136 |
| domain | Neutrophil cytosol factor 1, PX domain | 6 - 123 | IPR034909 |
| domain | Neutrophil cytosol factor 1, first SH3 domain | 160 - 212 | IPR035756 |
| domain | Neutrophil cytosol factor 1, second SH3 domain | 230 - 282 | IPR035757 |
7 GO annotations of cellular component
| Name | Definition |
|---|---|
| axon | The long process of a neuron that conducts nerve impulses, usually away from the cell body to the terminals and varicosities, which are sites of storage and release of neurotransmitter. |
| basolateral plasma membrane | The region of the plasma membrane that includes the basal end and sides of the cell. Often used in reference to animal polarized epithelial membranes, where the basal membrane is the part attached to the extracellular matrix, or in plant cells, where the basal membrane is defined with respect to the zygotic axis. |
| dendrite | A neuron projection that has a short, tapering, morphology. Dendrites receive and integrate signals from other neurons or from sensory stimuli, and conduct nerve impulses towards the axon or the cell body. In most neurons, the impulse is conveyed from dendrites to axon via the cell body, but in some types of unipolar neuron, the impulse does not travel via the cell body. |
| HCN channel complex | A cation ion channel with a preference for K+ over Na+ ions, which is activated by membrane hyperpolarization, and consists of a tetramer of HCN family members. Some members of this family (HCN1, HCN2 and HCN4) are also activated when cAMP binds to their cyclic nucleotide binding domain (CNBD). Channel complexes of this family play an important role in the control of pacemaker activity in the heart. |
| neuronal cell body | The portion of a neuron that includes the nucleus, but excludes cell projections such as axons and dendrites. |
| plasma membrane | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. |
| terminal bouton | Terminal inflated portion of the axon, containing the specialized apparatus necessary to release neurotransmitters. The axon terminus is considered to be the whole region of thickening and the terminal bouton is a specialized region of it. |
4 GO annotations of molecular function
| Name | Definition |
|---|---|
| cAMP binding | Binding to cAMP, the nucleotide cyclic AMP (adenosine 3',5'-cyclophosphate). |
| intracellularly cAMP-activated cation channel activity | Enables the transmembrane transfer of a cation by a channel that opens when intracellular cAMP has been bound by the channel complex or one of its constituent parts. |
| sodium channel activity | Enables the facilitated diffusion of a sodium ion (by an energy-independent process) involving passage through a transmembrane aqueous pore or channel without evidence for a carrier-mediated mechanism. |
| voltage-gated potassium channel activity | Enables the transmembrane transfer of a potassium ion by a voltage-gated channel. A voltage-gated channel is a channel whose open state is dependent on the voltage across the membrane in which it is embedded. |
8 GO annotations of biological process
| Name | Definition |
|---|---|
| cellular response to cAMP | Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a cAMP (cyclic AMP, adenosine 3',5'-cyclophosphate) stimulus. |
| in utero embryonic development | The process whose specific outcome is the progression of the embryo in the uterus over time, from formation of the zygote in the oviduct, to birth. An example of this process is found in Mus musculus. |
| monoatomic cation transport | The directed movement of a monoatomic cation, into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore. Monatomic cations (also called simple cations) are positively charged ions consisting of exactly one atom. |
| potassium ion transmembrane transport | A process in which a potassium ion is transported from one side of a membrane to the other. |
| regulation of heart contraction | Any process that modulates the frequency, rate or extent of heart contraction. Heart contraction is the process in which the heart decreases in volume in a characteristic way to propel blood through the body. |
| regulation of heart rate | Any process that modulates the frequency or rate of heart contraction. |
| regulation of membrane depolarization | Any process that modulates the rate, frequency or extent of membrane depolarization. Membrane depolarization is the process in which membrane potential changes in the depolarizing direction from the resting potential, usually from negative to positive. |
| sodium ion transmembrane transport | A process in which a sodium ion is transported from one side of a membrane to the other by means of some agent such as a transporter or pore. |
18 homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| Q9UL51 | HCN2 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 | Homo sapiens (Human) | SS |
| O60741 | HCN1 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 | Homo sapiens (Human) | SS |
| Q9P1Z3 | HCN3 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 | Homo sapiens (Human) | SS |
| Q9Y3Q4 | HCN4 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 | Homo sapiens (Human) | EV |
| O88703 | Hcn2 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 | Mus musculus (Mouse) | EV |
| O88704 | Hcn1 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 | Mus musculus (Mouse) | SS |
| O88705 | Hcn3 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 | Mus musculus (Mouse) | SS |
| Q9JKA9 | Hcn2 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 | Rattus norvegicus (Rat) | SS |
| Q9JKB0 | Hcn1 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 | Rattus norvegicus (Rat) | SS |
| Q9JKA8 | Hcn3 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 | Rattus norvegicus (Rat) | SS |
| Q9JKA7 | Hcn4 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 | Rattus norvegicus (Rat) | SS |
| A2ZX97 | Os01g0718700 | Potassium channel KAT6 | Oryza sativa subsp japonica (Rice) | PR |
| Q6K3T2 | Os02g0245800 | Potassium channel KAT1 | Oryza sativa subsp japonica (Rice) | PR |
| Q9SKD7 | CNGC3 | Probable cyclic nucleotide-gated ion channel 3 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q9LDR2 | CNGC19 | Putative cyclic nucleotide-gated ion channel 19 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q9SU64 | CNGC16 | Probable cyclic nucleotide-gated ion channel 16 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| P92960 | ATHB-4 | Potassium channel KAT3 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q39128 | KAT1 | Potassium channel KAT1 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| 10 | 20 | 30 | 40 | 50 | 60 |
| MDKLPPSMRK | RLYSLPQQVG | AKAWIMDEEE | DGEEEGAGGR | QDPSRRSIRL | RPLPSPSPSV |
| 70 | 80 | 90 | 100 | 110 | 120 |
| AAGCSESRGA | ALGATESEGP | GRSAGKSSTN | GDCRRFRGSL | ASLGSRGGGS | GGAGGGSSLG |
| 130 | 140 | 150 | 160 | 170 | 180 |
| HLHDSAEERR | LIAAEGDASP | GEDRTPPGLA | TEPERPATAA | QPAASPPPQQ | PPQPASASCE |
| 190 | 200 | 210 | 220 | 230 | 240 |
| QPSADTAIKV | EGGAAAIDHI | LPEAEVRLGQ | SGFMQRQFGA | MLQPGVNKFS | LRMFGSQKAV |
| 250 | 260 | 270 | 280 | 290 | 300 |
| EREQERVKSA | GFWIIHPYSD | FRFYWDLTML | LLMVGNLIII | PVGITFFKDE | NTTPWIVFNV |
| 310 | 320 | 330 | 340 | 350 | 360 |
| VSDTFFLIDL | VLNFRTGIVV | EDNTEIILDP | QRIKMKYLKS | WFVVDFISSI | PVEYIFLIVE |
| 370 | 380 | 390 | 400 | 410 | 420 |
| TRIDSEVYKT | ARAVRIVRFT | KILSLLRLLR | LSRLIRYIHQ | WEEIFHMTYD | LASAVVRIVN |
| 430 | 440 | 450 | 460 | 470 | 480 |
| LIGMMLLLCH | WDGCLQFLVP | MLQDFPHDCW | VSINGMVNNS | WGKQYSYALF | KAMSHMLCIG |
| 490 | 500 | 510 | 520 | 530 | 540 |
| YGRQAPVGMS | DVWLTMLSMI | VGATCYAMFI | GHATALIQSL | DSSRRQYQEK | YKQVEQYMSF |
| 550 | 560 | 570 | 580 | 590 | 600 |
| HKLPPDTRQR | IHDYYEHRYQ | GKMFDEESIL | GELSEPLREE | IINFNCRKLV | ASMPLFANAD |
| 610 | 620 | 630 | 640 | 650 | 660 |
| PNFVTSMLTK | LRFEVFQPGD | YIIREGTIGK | KMYFIQHGVV | SVLTKGNKET | RLADGSYFGE |
| 670 | 680 | 690 | 700 | 710 | 720 |
| ICLLTRGRRT | ASVRADTYCR | LYSLSVDNFN | EVLEEYPMMR | KKNSILLHKV | QHDLNSGVFN |
| 730 | 740 | 750 | 760 | 770 | 780 |
| YQENEIIQQI | VRHDREMAHC | AHRVQAAASA | TPTPTPVIWT | PLIQAPLQAA | AATTSVAIAL |
| 790 | 800 | 810 | 820 | 830 | 840 |
| THHPRLPAAI | FRPPPGPGLG | NLGAGQTPRH | PRRLQSLIPS | ALGSASPASS | PSQVDTPSSS |
| 850 | 860 | 870 | 880 | 890 | 900 |
| SFHIQQLAGF | SAPPGLSPLL | PSSSSSPPPG | ACGSPPAPTP | STSTAAAAST | TGFGHFHKAL |
| 910 | 920 | 930 | 940 | 950 | 960 |
| GGSLSSSDSP | LLTPLQPGAR | SPQAAQPPPP | LPGARGGLGL | LEHFLPPPPS | SRSPSSSPGQ |
| 970 | 980 | 990 | 1000 | 1010 | 1020 |
| LGQPPGELSL | GLAAGPSSTP | ETPPRPERPS | FMAGASGGAS | PVAFTPRGGL | SPPGHSPGPP |
| 1030 | 1040 | 1050 | 1060 | 1070 | 1080 |
| RTFPSAPPRA | SGSHGSLLLP | PASSPPPPQV | PQRRGTPPLT | PGRLTQDLKL | ISASQPALPQ |
| 1090 | 1100 | 1110 | 1120 | 1130 | 1140 |
| DGAQTLRRAS | PHSSGESVAA | FSLYPRAGGG | SGSSGGLGPP | GRPYGAIPGQ | HVTLPRKTSS |
| 1150 | 1160 | 1170 | 1180 | ||
| GSLPPPLSLF | GARAASSGGP | PLTTAAPQRE | PGARSEPVRS | KLPSNL |