1.A.84  The Calcium Homeostasis Modulator Ca2+ Channel (CALHM-C) Family

CALHM1 (calcium homeostasis modulator 1) forms a plasma membrane ion channel that mediates neuronal excitability in response to changes in extracellular Ca2 concentrations (Ma et al. 2012). Six human CALHM homologs exist with no homology to other proteins in humans, although CALHM1 is conserved across numerous species. Siebert et al. (2013) demonstrated that CALHM1 shares functional, quaternary and secondary structural similarities with connexins and evolutionarily distinct innexins and their vertebrate pannexin homologs. A CALHM1 channel is a hexamer, comprised of six monomers, each of which possesses four transmembrane domains, cytoplasmic amino and carboxyl termini, an amino-terminal helix, and conserved extracellular cysteines. The estimated pore diameter of the CALHM1 channel is 14 Å, enabling permeation of large charged molecules. Thus, CALHMs, connexins, pannexins and innexins are structurally related protein families with shared and distinct functional properties.  CALHM1 reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress (Gallego-Sandín et al. 2011).

CALHM1 P86L polymorphism has been shown to be a risk factor for Alzheimer''s disease in the Chinese population (Cui et al. 2010), Japanese population (Shibata et al. 2010), and Iranian population (Aqdam et al. 2010). The CALHM1 P86L polymorphism is associated with late-onset Alzheimer''s disease in a recessive model (Boada et al., 2010). Genetic variability of the gene cluster CALHM 1-3 also manifests itself in sporadic Creutzfeldt-Jakob disease (Calero et al., 2012). Moreover, a polymorphism in CALHM1 is associated with temporal lobe epilepsy (Lv et al. 2011).  The CALHM1 P86L polymorphism modulates CSF Aβ levels in cognitively healthy individuals at risk for Alzheimer''''s disease (Koppel et al. 2011). A Calhm1 knockout mouse has been generated and described (Wu et al. 2012). CALHM1 controls Ca2 -dependent MEK/ERK/RSK/MSK signaling in neurons (Dreses-Werringloer et al. 2013) and mediates purinergic neurotransmission of sweet, bitter and umami tastes (Taruno et al. 2013). 

CALHM1, formerly known as FAM26C, and its C. elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca2+ concentration ([Ca2+]o). In the presence of physiological [Ca2+]o ( approximately 1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations (Ma et al. 2015). Reducing [Ca2+]o increases channel open probability, enabling channel activation at negative membrane potentials. Thus, together, voltage and [Ca2+]o allosterically regulate CALHM channel gating. 

A CALHM1 channel is a hexamer of CALHM1 monomers with a functional pore diameter of approximately 14 Å. CALHM channels discriminate poorly among cations and anions, with signaling molecules including Ca2+ and ATP able to permeate through its pore. CALHM1 is expressed in the brain where it plays an important role in cortical neuron excitability induced by low [Ca2+]o and in type II taste bud cells in the tongue that sense sweet, bitter, and umami tastes where it functions as an essential ATP release channel to mediate nonsynaptic neurotransmitter release. CLHM-1 is expressed in C. elegans sensory neurons and body wall muscles, and its genetic deletion causes locomotion defects (Ma et al. 2015).

Ions and ATP permeate these CALHM channels in a voltage- dependent manner to control neuronal excitability, taste signaling and the pathologies of depression and Alzheimer's disease. (Syrjanen et al. 2020) revealed the structures of two CALHMs, chicken CALHM1 and human CALHM2, by single-particle cryo-electron microscopy (cryo-EM). These structures showed a novel assembly of four transmembrane helices into channels of octamers and undecamers, respectively. Molecular dynamics simulations suggest that lipids can favorably assemble into a bilayer within the larger CALHM2 pore, but not within CALHM1, demonstrating the potential correlation between pore size, lipid accommodation and channel activity (Syrjanen et al. 2020).

The reactions catalyezd by CALHM1 is:

Ca2+ (in) ⇌ Ca2+ (out)

ions (in)  ⇌ ions (out)

ATP (in) ⇌ ATP (out)

This family belongs to the Tetraspan Junctional Complex Protein (4JC) Superfamily.



Aqdam, M.J., K. Kamali, M. Rahgozar, M. Ohadi, M. Manoochehri, A. Tahami, L. Bostanshirin, and H.R. Khorshid. (2010). Association of CALHM1 Gene Polymorphism with Late Onset Alzheimer's Disease in Iranian Population. Avicenna J Med Biotechnol 2: 153-157.

Boada, M., C. Antúnez, J. López-Arrieta, J.J. Galán, F.J. Morón, I. Hernández, J. Marín, P. Martínez-Lage, M. Alegret, J.M. Carrasco, C. Moreno, L.M. Real, A. González-Pérez, L. Tárraga, and A. Ruiz. (2010). CALHM1 P86L polymorphism is associated with late-onset Alzheimer's disease in a recessive model. J Alzheimers Dis 20: 247-251.

Calero, O., M.J. Bullido, J. Clarimón, R. Hortigüela, A. Frank-García, P. Martínez-Martín, A. Lleó, M.J. Rey, I. Sastre, A. Rábano, J. de Pedro-Cuesta, I. Ferrer, and M. Calero. (2012). Genetic variability of the gene cluster CALHM 1-3 in sporadic Creutzfeldt-Jakob disease. Prion 6: 407-412.

Choi, W., N. Clemente, W. Sun, J. Du, and W. Lü. (2019). The structures and gating mechanism of human calcium homeostasis modulator 2. Nature 576: 163-167.

Cui, P.J., L. Zheng, L. Cao, Y. Wang, Y.L. Deng, G. Wang, W. Xu, H.D. Tang, J.F. Ma, T. Zhang, J.Q. Ding, Q. Cheng, and S.D. Chen. (2010). CALHM1 P86L polymorphism is a risk factor for Alzheimer's disease in the Chinese population. J Alzheimers Dis 19: 31-35.

Dreses-Werringloer U., Vingtdeux V., Zhao H., Chandakkar P., Davies P. and Marambaud P. (2013). CALHM1 controls the Ca(2)(+)-dependent MEK, ERK, RSK and MSK signaling cascade in neurons. J Cell Sci. 126(Pt 5):1199-206.

Dreses-Werringloer, U., J.C. Lambert, V. Vingtdeux, H. Zhao, H. Vais, A. Siebert, A. Jain, J. Koppel, A. Rovelet-Lecrux, D. Hannequin, F. Pasquier, D. Galimberti, E. Scarpini, D. Mann, C. Lendon, D. Campion, P. Amouyel, P. Davies, J.K. Foskett, F. Campagne, and P. Marambaud. (2008). A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell 133: 1149-1161.

Gallego-Sandín, S., M.T. Alonso, and J. García-Sancho. (2011). Calcium homoeostasis modulator 1 (CALHM1) reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress. Biochem. J. 437: 469-475.

Koppel, J., F. Campagne, V. Vingtdeux, U. Dreses-Werringloer, M. Ewers, D. Rujescu, H. Hampel, M.L. Gordon, E. Christen, J. Chapuis, B.S. Greenwald, P. Davies, and P. Marambaud. (2011). CALHM1 P86L polymorphism modulates CSF Aβ levels in cognitively healthy individuals at risk for Alzheimer's disease. Mol Med 17: 974-979.

Lv, R.J., J.S. He, Y.H. Fu, X.Q. Shao, L.W. Wu, Q. Lu, L.R. Jin, and H. Liu. (2011). A polymorphism in CALHM1 is associated with temporal lobe epilepsy. Epilepsy Behav 20: 681-685.

Ma, Z., A.P. Siebert, K.H. Cheung, R.J. Lee, B. Johnson, A.S. Cohen, V. Vingtdeux, P. Marambaud, and J.K. Foskett. (2012). Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. Proc. Natl. Acad. Sci. USA 109: E1963-1971.

Ma, Z., J.E. Tanis, A. Taruno, and J.K. Foskett. (2015). Calcium homeostasis modulator (CALHM) ion channels. Pflugers Arch. [Epub: Ahead of Print]

Malik, U., A. Javed, A. Ali, and K. Asghar. (2016). Structural and functional annotation of human FAM26F: A multifaceted protein having a critical role in the immune system. Gene. [Epub: Ahead of Print]

Romanov, R.A., R.S. Lasher, B. High, L.E. Savidge, A. Lawson, O.A. Rogachevskaja, H. Zhao, V.V. Rogachevsky, M.F. Bystrova, G.D. Churbanov, I. Adameyko, T. Harkany, R. Yang, G.J. Kidd, P. Marambaud, J.C. Kinnamon, S.S. Kolesnikov, and T.E. Finger. (2018). Chemical synapses without synaptic vesicles: Purinergic neurotransmission through a CALHM1 channel-mitochondrial signaling complex. Sci Signal 11:.

Shibata, N., B. Kuerban, M. Komatsu, T. Ohnuma, H. Baba, and H. Arai. (2010). Genetic association between CALHM1, 2, and 3 polymorphisms and Alzheimer's disease in a Japanese population. J Alzheimers Dis 20: 417-421.

Siebert, A.P., Z. Ma, J.D. Grevet, A. Demuro, I. Parker, and J.K. Foskett. (2013). Structural and Functional Similarities of Calcium Homeostasis Modulator 1 (CALHM1) Ion Channel with Connexins, Pannexins, and Innexins. J. Biol. Chem. 288: 6140-6153.

Syrjanen, J.L., K. Michalski, T.H. Chou, T. Grant, S. Rao, N. Simorowski, S.J. Tucker, N. Grigorieff, and H. Furukawa. (2020). Structure and assembly of calcium homeostasis modulator proteins. Nat Struct Mol Biol 27: 150-159.

Taruno A., Vingtdeux V., Ohmoto M., Ma Z., Dvoryanchikov G., Li A., Adrien L., Zhao H., Leung S., Abernethy M., Koppel J., Davies P., Civan MM., Chaudhari N., Matsumoto I., Hellekant G., Tordoff MG., Marambaud P. and Foskett JK. (2013). CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature. 495(7440):223-6.

Taruno, A., H. Sun, K. Nakajo, T. Murakami, Y. Ohsaki, M.A. Kido, F. Ono, and Y. Marunaka. (2017). Post-translational palmitoylation controls the voltage gating and lipid raft association of the CALHM1 channel. J. Physiol. [Epub: Ahead of Print]

Workman, A.D., R.M. Carey, B. Chen, C.J. Saunders, P. Marambaud, C.H. Mitchell, M.G. Tordoff, R.J. Lee, and N.A. Cohen. (2017). CALHM1-Mediated ATP Release and Ciliary Beat Frequency Modulation in Nasal Epithelial Cells. Sci Rep 7: 6687.

Wu, J., S. Peng, R. Wu, Y. Hao, G. Ji, and Z. Yuan. (2012). Generation of Calhm1 knockout mouse and characterization of calhm1 gene expression. Protein Cell 3: 470-480.


TC#NameOrganismal TypeExample

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 reviewed 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 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. 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) peptides 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.


CALHM1 of Homo sapiens (Q8IU99)


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. 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).


CALHM2 of Homo sapiens (Q9HA72)


The human calcium homeostasis modulator protein 3, CALHM3 or FAM26A, of 344 aas and 4 TMSs/


CALHM3 of Homo sapiens (Q86XJ0)


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. 


CALHM-1 of Caenorhabditis elegans (Q18593)


CALHM4 or FAM26D of 314 aas and 4 TMSs


FAM26D of Homo sapiens (Q5JW98)


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).

CALHM6 of Homo sapiens


CALHM5 of 309 aas and 4 or 5 TMSs. The channel function has not been characterized as of Feb. 2020.

CALHM5 of Homo sapiens


Uncharacterized protein of 1457 aas with about 850 hydrophilic N-terminal aas and 8 C-terminal TMSs in a 4 + 4 arrangement.

UP of Hirundo rustica rustica


TC#NameOrganismal TypeExample

Sea anemone CALHM homologue


CALHM homologue of Nematostella vectensis


Uncharacterized protein of 304 aas and 4 TMSs.

UP of Nematostella vectensis (Starlet sea anemone)


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.

UP of Stylophora pistillata


Calcium homeostasis modulator protein 5-like of 362 aas and 4 or 5 TMSs.

CALHM protein of Actinia tenebrosa


Uncharacterized protein of 356 aas and 4 or 5 TMSs.

UP of Pocillopora damicornis


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).

UP of Pelodiscus sinensis (Chinese soft-shelled turtle)


Uncharacterized protein of 329 aas and 4 TMSs.

UP of Henneguya salminicola


Uncharacterized protein of 275 aas and 4 TM

UP of Salmo trutta (river trout)


Uncharacterized protein of 431 aas and 4 TMSs

UP of Pygocentrus nattereri (red-bellied piranha)


TC#NameOrganismal TypeExample

Uncharacterized protein of 328 aas and 4 TMSs

UP of Sander lucioperca (pike-perch)


Uncharacterized protein of 494 aas with 4 N-terminal TMSs and an long hydrophilic domain with one C-terminal TMS

UP of Oryzias latipes (Japanese medaka)


Uncharacterized protein of 268 aas and 4 TMSs

UP of Archocentrus centrarchus (flier cichlid)


Uncharacterized protein of 311 aas and 4 TMSs.

UP of Anabas testudineus (climbing perch)


Uncharacterized protein of 290 aas and 4 TMSs.

UP of Astatotilapia calliptera (eastern happy)


Uncharacterized protein of 332 aas and 4 N-terminal TMSs

UP of Erpetoichthys calabaricus (reedfish)


TC#NameOrganismal TypeExample

Uncharacterized protein of 312 aas and 4 TMSs

UP of Pomacea canaliculata


Uncharacterized protein of 385 aas and 4 N-terminal TMSs.

UP of Pomacea canaliculata


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).

UP of Pomacea canaliculata


TC#NameOrganismal TypeExample