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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).

The reaction catalyezd by CALHM1 is:

Ca2+ (in) → Ca2+ (out)

References associated with 1.A.84 family:

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. 23408664
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. 20164592
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. 22874670
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. 20061624
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. 23345406
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. 18585350
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. 21574960
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. 21629967
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. 21439911
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. 22711817
Ma, Z., J.E. Tanis, A. Taruno, and J.K. Foskett. (2015). Calcium homeostasis modulator (CALHM) ion channels. Pflugers Arch. [Epub: Ahead of Print] 26603282
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] 27784631
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. 20164573
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. 23300080
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. 23467090
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. 22723178