| TCID | Name | Domain | Kingdom/Phylum | Protein(s) |
|---|---|---|---|---|
|
1.A.84.1.1 | The human calcium homeostasis modulator protein 1, CALHM1 or FAM16C of 346 aas and 5 TMSs (Dreses-Werringloer et al. 2008). The P86L polymorphism increases Abeta levels and may influence Alzheimer's disease risk by interfering with CALHM1-mediated Ca2+ permeability (Dreses-Werringloer et al. 2008). The characteristics of this channel have been studied (Ma et al. 2012) and reviewed (Ma et al. 2015). Post-translational palmitoylation controls the voltage-gating and lipid raft association (Taruno et al. 2017). CALHM1 plays a role, complementary to PANX1 (TC#1.A.25.2.1), in ATP release and downstream ciliary beat frequency modulation following a mechanical stimulus in airway epithelial cells (Workman et al. 2017). CALHM1 is required for sensory perception of sweet, bitter and umami tastes. It is present in type II taste bud cells, where it plays a central role in taste perception by inducing ATP release from the cell with ATP acting as a neurotransmitter to activate afferent neural gustatory pathways. It acts both as a voltage-gated and calcium-activated ion channel mediating neuronal excitability in response to changes in extracellular Ca2+ concentration (Bhat et al. 2021). It has poor ion selectivity and forms a wide pore (around 14 Å) that mediates permeation of Ca2+, Na+ and K+, as well as monovalent anions. It acts as an activator of the ERK1 and ERK2 cascade and triggers endoplasmic reticulum stress by reducing the calcium content of the ER (Gallego-Sandín et al. 2011). It may indirectly control amyloid precursor protein (APP) proteolysis and aggregated amyloid-beta (Abeta) peptide levels in a Ca2+ dependent manner (Dreses-Werringloer et al. 2008). The ATP comes from unusually large mitochondria that are adjacent to clusters of CALHM1 channels in the plasma membrane (Romanov et al. 2018). Thus, neurotransmission does not rely on vesicle formation. Intramolecular disulfide bonds for biogenesis of CALHM1 ion channels are dispensable for voltage-dependent activation (Kwon et al. 2021). Intracellular Ca2+ oscillation frequency and amplitude modulation mediate epithelial apical and basolateral membranes crosstalk (Hassan et al. 2024).
| Eukaryota |
Metazoa, Chordata | CALHM1 of Homo sapiens (Q8IU99) |
|
1.A.84.1.2 | The human calcium homeostasis modulator protein 2, CALHM2 or FAM16B, of 323 aas and 4 or 5 TMSs. The structures and gating mechanism of CALHM2 have been reported (Choi et al. 2019). Cryo-EM structures in the Ca2+-free active or open state and in the ruthenium red (RUR)-bound inhibited state, have been solved at 2.7 Å resolution (see also Syrjanen et al. 2020 and Demura et al. 2020. Purified CALHM2 channels form both gap junctions and undecameric hemichannels. The protomer shows a mirrored arrangement of the TMSs (helices S1-S4) relative to other channels with a similar topology, such as connexins, innexins and volume-regulated anion channels. Upon binding to RUR, a contracted pore with notable conformational changes of the pore-lining helix S1 was observed, which swings nearly 60 degrees towards the pore axis from a vertical to a lifted position. Possibly a two-section gating mechanism is operative in which the S1 helix coarsely adjusts, and the N-terminal helix fine-tunes, the pore size (Choi et al. 2019). The Kilifish CALHM1 octameric structure reveals that the N-terminal helix forms the constriction site at the channel pore in the open state and modulates the ATP conductance. The CALHM2 undecamer and CLHM-1 nonamer structures show different oligomeric stoichiometries among CALHM homologs. The cryo-EM structures of a chimeric construct revealed that the intersubunit interactions in the transmembrane region and the TMS-intracellular domain linker define the oligomeric stoichiometry (Demura et al. 2020). | Eukaryota |
Metazoa, Chordata | CALHM2 of Homo sapiens (Q9HA72) |
|
1.A.84.1.3 | The human calcium homeostasis modulator protein 3, CALHM3 or FAM26A, of 344 aas and 4 TMSs/ | Eukaryota |
Metazoa, Chordata | CALHM3 of Homo sapiens (Q86XJ0) |
|
1.A.84.1.4 | Calcium homeostasis modulator 1 (CALHM1 or FAM26C) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability (Ma et al. 2015). CALHM1 (CALHM-1 or CLHM-1) is of 329 aas and exhibits 4 or 5 TMSs. This protein forms a protein complex, assembling into voltage-gated, Ca2+-sensitive, nonselective channels. These complexes contain an ion-conduction pore sufficiently wide to permit the passing of ATP molecules serving as neurotransmitters. Calcium homeostasis modulators (CALHMs/CLHMs) comprise a family of pore-forming protein complexes assembling into voltage-gated, Ca2+-sensitive, nonselective channels. These complexes contain an ion-conduction pore sufficiently wide to permit the passing of ATP molecules serving as neurotransmitters. Yang et al. 2020 and Demura et al. 2020 presented the structure of the Caenorhabditis elegans CLHM1 channel (1.A.84.1.4) in its open state, solved through single-particle cryo-EM at 3.7Å resolution. The transmembrane region of the channel structure of the dominant class shows an assembly of tenfold rotational symmetry in one layer, and its cytoplasmic region is involved in additional twofold symmetrical packing in a tail-to-tail manner. A series of amino acyl residues are critical for the regulation of the channel. presented the structure of the channel in its open state, solved through single-particle cryo-EM at 3.7Å resolution. The transmembrane region of the channel shows an assembly of tenfold rotational symmetry in one layer, and its cytoplasmic region is involved in additional twofold symmetrical packing in a tail-to-tail manner. A series of amino acyl residues are critical for regulation of the channel (Calcium homeostasis modulators (CALHMs/CLHMs) comprise a family of pore-forming protein complexes assembling into voltage-gated, Ca2+-sensitive, nonselective channels. These complexes contain an ion-conduction pore sufficiently wide to permit the passing of ATP molecules serving as neurotransmitters. Yang et al. 2020 presented the structure of the Caenorhabditis elegans CLHM1 channel (1.A.84.1.4) in its open state, solved through single-particle cryo-EM at 3.7Å resolution. The transmembrane region of the channel structure of the dominant class shows an assembly of tenfold rotational symmetry in one layer, and its cytoplasmic region is involved in additional twofold symmetrical packing in a tail-to-tail manner. A series of amino acyl residues are critical for regulation of the channel (Yang et al. 2020). | Eukaryota |
Metazoa, Nematoda | CALHM-1 of Caenorhabditis elegans (Q18593) |
|
1.A.84.1.5 | CALHM4 or FAM26D of 314 aas and 4 TMSs | Eukaryota |
Metazoa, Chordata | FAM26D of Homo sapiens (Q5JW98) |
|
1.A.84.1.6 | The CALHM6 or FAM26F channel protein of 315 aas and probably 5 TMSs. FAM26F (family with sequence similarity 26, member F) plays an important role in diverse immune responses (Malik et al. 2016). | Eukaryota |
Metazoa, Chordata | CALHM6 of Homo sapiens |
|
1.A.84.1.7 | Calcium homeostasis modulators (CALHMs) are ATP release channels that play crucial roles in neurons including gustatory signaling and neuronal excitability. Pathologies of Alzheimer's disease and depression have been associated with the dysfunction of CALHMs (see TC# 1.A.84.1.1). CALHM5 structures, solved by cryoEM, showed an abnormally large pore channel structure assembled as an undecamer with four transmembrane helices (TMS1-TMS4), an N-terminal helix (NTH), an extracellular loop region and an intracellular C-terminal domain (CTD) that consists of three α-helices, CH1-3. The TMS1 and NTH were poorly defined among other CALHMs, but these regions were well defined in the CALHM5 channel structure (Bhat et al. 2021). | Eukaryota |
Metazoa, Chordata | CALHM5 of Homo sapiens |
|
1.A.84.1.8 | Uncharacterized protein of 1457 aas with about 850 hydrophilic N-terminal aas and 8 C-terminal TMSs in a 4 + 4 arrangement. | Eukaryota |
Metazoa, Chordata | UP of Hirundo rustica rustica |
|
1.A.84.1.9 | Killifish CALHM1 of 351 aas and 5 TMSs in a 2 + 2 + 1 TMS arrangement. The cryoEM structure has been determined to 2.66 Å resolution (Demura et al. 2020). The human CALHM-2 (CALMH2) and the C. elegans CLHM-1 (CLHM1) were also solved at lower resolution. The CALHM1 octameric structure reveals that the N-terminal helix forms the constriction site at the channel pore in the open state and modulates the ATP conductance. The CALHM2 undecamer and CLHM-1 nonamer structures show the different oligomeric stoichiometries among CALHM homologs. The cryo-EM structures of the chimeric construct revealed that the intersubunit interactions in the transmembrane region and the TMS-intracellular domain linker define the oligomeric stoichiometry (Demura et al. 2020). | Eukaryota |
Metazoa, Chordata | CALHM1 of Oryzias latipes (Japanese rice fish) (Japanese killifish) |
|
1.A.84.1.10 | CALHM1 of 346 aas and 4 or 5 TMSs. A cryo-EM structure of full-length Ca2+-free CALHM1 from Danio rerio at an overall resolution of 3.1 Å has been published (Ren et al. 2020). The structure reveals an octameric architecture with a wide pore diameter of ~20 Å, presumably representing the active conformation. The structure is substantially different from that of the isoform CALHM2, which forms both undecameric hemichannels and gap junctions. The N-terminal small helix folds back to the pore and forms an antiparallel interaction with TMS 1. Structural analysis revealed that the extracellular loop 1 region within the dimer interface may contribute to oligomeric assembly. A positive potential belt inside the pore was identified that may modulate ion permeation (Ren et al. 2020). | Eukaryota |
Metazoa, Chordata | CALHM1 of Danio rerio (Zebrafish) (Brachydanio rerio) |
|
1.A.84.2.1 | Sea anemone CALHM homologue | Eukaryota |
Metazoa, Cnidaria | CALHM homologue of Nematostella vectensis |
|
1.A.84.2.2 | Uncharacterized protein of 304 aas and 4 TMSs. | Eukaryota |
Metazoa, Cnidaria | UP of Nematostella vectensis (Starlet sea anemone) |
|
1.A.84.2.3 | Uncharacterized protein of 769 aas and 8 TMSs in a 4 + 4 TMS arrangement, with each 3 TMS unit followed by a hydrophilic region of about 180 aas. | Eukaryota |
Metazoa, Cnidaria | UP of Stylophora pistillata |
|
1.A.84.2.4 | Calcium homeostasis modulator protein 5-like of 362 aas and 4 or 5 TMSs. | Eukaryota |
Metazoa, Cnidaria | CALHM protein of Actinia tenebrosa |
|
1.A.84.2.5 | Uncharacterized protein of 356 aas and 4 or 5 TMSs. | Eukaryota |
Metazoa, Cnidaria | UP of Pocillopora damicornis |
|
1.A.84.2.6 | Uncharacterized protein of 435 aas and 4 N-terminal TMSs (the FAM26 domain) followed by a hydrophilic region that shows sequence similarity with 9.B.96.1.1 (e-7). | Eukaryota |
Metazoa, Chordata | UP of Pelodiscus sinensis (Chinese soft-shelled turtle) |
|
1.A.84.2.7 | Uncharacterized protein of 329 aas and 4 TMSs. | Eukaryota |
Metazoa, Cnidaria | UP of Henneguya salminicola |
|
1.A.84.2.8 | Uncharacterized protein of 275 aas and 4 TM | Eukaryota |
Metazoa, Chordata | UP of Salmo trutta (river trout) |
|
1.A.84.2.9 | Uncharacterized protein of 431 aas and 4 TMSs | Eukaryota |
Metazoa, Chordata | UP of Pygocentrus nattereri (red-bellied piranha) |
|
1.A.84.3.1 | Uncharacterized protein of 328 aas and 4 TMSs | Eukaryota |
Metazoa, Chordata | UP of Sander lucioperca (pike-perch) |
|
1.A.84.3.2 | Uncharacterized protein of 494 aas with 4 N-terminal TMSs and an long hydrophilic domain with one C-terminal TMS | Eukaryota |
Metazoa, Chordata | UP of Oryzias latipes (Japanese medaka) |
|
1.A.84.3.3 | Uncharacterized protein of 268 aas and 4 TMSs | Eukaryota |
Metazoa, Chordata | UP of Archocentrus centrarchus (flier cichlid) |
|
1.A.84.3.4 | Uncharacterized protein of 311 aas and 4 TMSs. | Eukaryota |
Metazoa, Chordata | UP of Anabas testudineus (climbing perch) |
|
1.A.84.3.5 | Uncharacterized protein of 290 aas and 4 TMSs. | Eukaryota |
Metazoa, Chordata | UP of Astatotilapia calliptera (eastern happy) |
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1.A.84.3.6 | Uncharacterized protein of 332 aas and 4 N-terminal TMSs | Eukaryota |
Metazoa, Chordata | UP of Erpetoichthys calabaricus (reedfish) |
|
1.A.84.4.1 | Uncharacterized protein of 312 aas and 4 TMSs | Eukaryota |
Metazoa, Mollusca | UP of Pomacea canaliculata |
|
1.A.84.4.2 | Uncharacterized protein of 385 aas and 4 N-terminal TMSs. | Eukaryota |
Metazoa, Mollusca | UP of Pomacea canaliculata |
|
1.A.84.4.3 | Uncharacterized protein of 278 aas and 4 TMSs. This protein shows substantial sequence similarity with TC#s 1.A.84.1.8, 1.7 and 1.5 (up to e-6). | Eukaryota |
Metazoa, Mollusca | UP of Pomacea canaliculata |