1.A.37 The CD20 Ca2+ Channel (CD20) Family

The B-lymphocyte differentiation antigen, CD20 (also called B1, Leu-16 and BP35), is a protein of 297 aas with 4 TMSs (Tedder et al., 1989). Both the N- and C-termini are in the cytoplasm. The protein is phosphorylated by one or more ser/thr protein kinases that may regulate its role in B-cell activation and proliferation. Transfection of CD20 into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes (Bubien et al., 1993). The CD20 Ca2+-permeable cation channel expressed in Balb/c3T3 cells is activated by insulin-like growth factor and the α-subunits of G-proteins (Kanzaki et al., 1997a,b). It is a store-operated calcium entry modulator in skeletal muscle (Parolini et al. 2012). Homologues include the high affinity IgE receptor, the testes development regulated protein NYD-SP21 and the Chandra protein. Homologues with BLAST scores above threshold are found only in mammals.



Boulay, A.C., B. Saubaméa, S. Cisternino, V. Mignon, A. Mazeraud, L. Jourdren, C. Blugeon, and M. Cohen-Salmon. (2015). The Sarcoglycan complex is expressed in the cerebrovascular system and is specifically regulated by astroglial Cx30 channels. Front Cell Neurosci 9: 9.

Brown, A.A., J. Jensen, Y.S. Nikolova, S. Djurovic, I. Agartz, A. Server, R.E. Ferrell, S.B. Manuck, M. Mattingsdal, I. Melle, A.R. Hariri, A. Frigessi, and O.A. Andreassen. (2012). Genetic variants affecting the neural processing of human facial expressions: evidence using a genome-wide functional imaging approach. Transl Psychiatry 2: e143.

Bubien, J.K., L.J. Zhou, P.D. Bell, R.A. Frizzell, and T.F. Tedder. (1993). Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J. Cell Biol. 121: 1121-1132.

Cohn, R.D., M. Durbeej, S.A. Moore, R. Coral-Vazquez, S. Prouty, and K.P. Campbell. (2001). Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex. J Clin Invest 107: R1-7.

Kang, C., R. Rostoker, S. Ben-Shumel, R. Rashed, J.A. Duty, D. Demircioglu, I.M. Antoniou, L. Isakov, Z. Shen-Orr, J.J. Bravo-Cordero, N. Kase, M.P. Cuajungco, T.M. Moran, D. LeRoith, and E.J. Gallagher. (2021). TMEM176B Regulates AKT/mTOR Signaling and Tumor Growth in Triple-Negative Breast Cancer. Cells 10:.

Kanzaki, M., L. Nie, H. Shibata, and I. Kojima. (1997a). Activation of a calcium-permeable cation channel CD20 expressed in Balb/c3T3 cells by insulin-like growth factor-I. J. Biol. Chem. 272: 4964-4969.

Kanzaki, M., M.A. Lindorfer, J.C. Garrison, and I. Kojima. (1997b). Activation of the calcium-permeable cation channel CD20 by alpha subunits of the Gi protein. J. Biol. Chem. 272: 14733-14739.

Li, H., M. Zhang, E. Linghu, F. Zhou, J.G. Herman, L. Hu, and M. Guo. (2018). Epigenetic silencing of TMEM176A activates ERK signaling in human hepatocellular carcinoma. Clin Epigenetics 10: 137.

Liu, W.B., F. Han, X. Jiang, H.Q. Chen, H. Zhao, Y. Liu, Y.H. Li, C. Huang, J. Cao, and J.Y. Liu. (2015). TMEM196 acts as a novel functional tumour suppressor inactivated by DNA methylation and is a potential prognostic biomarker in lung cancer. Oncotarget 6: 21225-21239.

McCourt, J.L., K.M. Stearns-Reider, H. Mamsa, P. Kannan, M.H. Afsharinia, C. Shu, E.M. Gibbs, K.M. Shin, Y.Z. Kurmangaliyev, L.R. Schmitt, K.C. Hansen, and R.H. Crosbie. (2023). Multi-omics analysis of sarcospan overexpression in mdx skeletal muscle reveals compensatory remodeling of cytoskeleton-matrix interactions that promote mechanotransduction pathways. Skelet Muscle 13: 1.

Parolini D., Cassinelli L., Razini P., Sitzia C., Tonna N., Erratico S., Colleoni F., Angeloni V., Maffioli E., Farini A., Maciotta S., Porretti L., Belicchi M., Bianco F., Tedeschi G., Meregalli M. and Torrente Y. (2012). Expression of CD20 reveals a new store-operated calcium entry modulator in skeletal muscle. Int J Biochem Cell Biol. 44(12):2095-105.

Penhallow, R.C., K. Class, H. Sonoda, J.B. Bolen, and R.B. Rowley. (1995). Temporal activation of nontransmembrane protein-tyrosine kinases following mast cell Fc epsilon RI engagement. J. Biol. Chem. 270: 23362-23365.

Rougé, L., N. Chiang, M. Steffek, C. Kugel, T.I. Croll, C. Tam, A. Estevez, C.P. Arthur, C.M. Koth, C. Ciferri, E. Kraft, J. Payandeh, G. Nakamura, J.T. Koerber, and A. Rohou. (2020). Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab. Science 367: 1224-1230.

Segovia, M., S. Russo, M. Jeldres, Y.D. Mahmoud, V. Perez, M. Duhalde, P. Charnet, M. Rousset, S. Victoria, F. Veigas, C. Louvet, B. Vanhove, R.A. Floto, I. Anegon, M.C. Cuturi, M.R. Girotti, G.A. Rabinovich, and M. Hill. (2019). Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation. Cancer Cell 35: 767-781.e6.

Segovia, M., S. Russo, M.R. Girotti, G.A. Rabinovich, and M. Hill. (2020). Role of inflammasome activation in tumor immunity triggered by immune checkpoint blockers. Clin Exp Immunol 200: 155-162.

Sun, Y., D. Zhang, G. Sun, Y. Lv, Y. Li, X. Li, Y. Song, J. Li, Z. Fan, and H. Wang. (2018). RNA-sequencing study of peripheral blood mononuclear cells in sporadic Ménière's disease patients: possible contribution of immunologic dysfunction to the development of this disorder. Clin Exp Immunol 192: 33-45.

Tedder, T.F., G. Klejman, S.F. Schlossman, and H. Saito. (1989). Structure of the gene encoding the human B lymphocyte differentiation antigen CD20 (B1). J. Immunol. 142: 2560-2568.

Zuccolo, J., J. Bau, S.J. Childs, G.G. Goss, C.W. Sensen, and J.P. Deans. (2010). Phylogenetic analysis of the MS4A and TMEM176 gene families. PLoS One 5: e9369.


TC#NameOrganismal TypeExample

The CD20 (Cluster of differentiation-20) protein (297 aas and 4 TMSs) is a putative cation channel (B-lymphocyte CD20 antigen) or an indirect regulator of calcium release.  The 3-d structure has been determined (Rougé et al. 2020). It is targeted by monoclonal antibodies for the treatment of malignancies and autoimmune disorders. Rituximab (RTX) activates complement to kill B cells.  Rougé et al. 2020 obtained a structure of CD20 in complex with RTX, revealing a compact double-barrel dimer bound by two RTX antigen-binding fragments (Fabs), each of which engages a composite epitope. RTX cross-links CD20 into circular assemblies and lead to a structural model for complement recruitment.


CD20 of Homo sapiens


Uncharacterized protein of 247 aas and 4 TMSs in a 3 + 1 TMS arrangement.

UP of Xiphophorus couchianus (Monterrey platyfish)


TC#NameOrganismal TypeExample

Membrane-spanning 4 TMS subfamily A member 10 (MS4A superfamily), HTm4


HTm4 of Homo sapiens (Q96PG2)


TC#NameOrganismal TypeExample

4 TMS testes development-related NYD-SP21 protein


NYD-SP21 of Homo sapiens (Q96JA4)


MS4A2 of 244 aas and 4 TMSs. High affinity receptor that binds to the Fc region of immunoglobulins epsilon. Aggregation of Fc epsilon receptor (FCERI) by multivalent antigens is required for the full mast cell response, including the release of preformed mediators (such as histamine) by degranulation and de novo production of lipid mediators and cytokines (Penhallow et al. 1995). Also mediates the secretion of important lymphokines. Binding of allergen to receptor-bound IgE leads to cell activation and the release of mediators responsible for the manifestations of allergy.

MS412 of Homo sapiens


Uncharacterized membrane-spanning 4-domain subfamily A member 4A-like protein of 261 aas and 4 or 5 TMSs in a 3 or 4 + 1 TMS arrangement.

UP of Cyprinus carpio


TC#NameOrganismal TypeExample

Fam189A1 or CD20 family with 539 aas and 4 TMSs.

CD20 family protein of Homo sapiens


Uncharacterized protein of 1323 aas and 4 TMSs in a 3 + 1 TMS arrangement at the N-terminus of this protein followed by a long hydrophilic region of ~1000 aas. The hydrophobic region of this protein shows significan sequence similarity with members of family TC# 9.B.200.

UP of Actinia tenebrosa (Australian red waratah sea anemone)


TC#NameOrganismal TypeExample

Sarcospan, SSPN, of 242 aas and 4 TMSs.  Part of the smooth muscle sarcoglycan-sarcospan  complex which in involved in idiopathic cardiomyopathy associated with myocardial ischemia (Cohn et al. 2001).  Regulated by astroglial connexin 30 channels (TC# 1.A.24.1.7; Boulay et al. 2015). Analysis of sarcospan overexpression in mdx skeletal muscle reveals compensatory remodeling of cytoskeleton-matrix interactions that promote mechanotransduction pathways (McCourt et al. 2023).

Sarcospan of Bos taurus


TC#NameOrganismal TypeExample

TMem196 of 185 aas and 4 TMSs,  Acts as a tumor suppressor (Liu et al. 2015).

TMem196 protein of Canis lupus familiaris (Dog) (Canis familiaris)


TC#NameOrganismal TypeExample

Transmembrane protein 212, TMEM212, of 194 aas and 4 or 5 TMSs (Brown et al. 2012).

TMEM212 of Homo sapiens


TC#NameOrganismal TypeExample

TMEM176B cation channel of 270 aas and 4 TMSs in a 3 + 1 TMS arrangement.  It is upregulated in Meniere's disease (Sun et al. 2018). Phylogenetic analyses of the MS4A and TMEM176 gene families have been reported (Zuccolo et al. 2010).  Pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers (Segovia et al. 2019). Inflammasome activation may reinforce anti-tumor immunity by boosting CD8(+) T cell priming as well as by enhancing T helper type 17 (Th17) responses. Modulation of TMEM176B provides one such mechanism, and this protein provides a potential target to unleash inflammasome activation, leading to reinforced anti-tumor immunity and improved efficacy of immune checkpoint blockers (Segovia et al. 2020). TMEM176B regulates AKT/mTOR signaling and tumor growth in triple-negative breast cancer (Kang et al. 2021).  A subpopulation of CD146(+) macrophages enhances antitumor immunity by activating the NLRP3 inflammasome, and this involves TMEM176B. 

TMEM176B of Homo sapiens


TMEM176A of 235 aas and 4 to 6 TMSs in a 3 or 4 TMS cluster followed by a 1 or 2 TMS cluster. Epigenetic silencing of TMEM176A activates ERK signaling in human hepatocellular carcinoma due to promoter methylation (Li et al. 2018).

TMEM176A of Homo sapiens


Uncharacterized protein of 244 aas and 5 TMSs in a 4 + 1 TMS arrangement.

UP of Carassius auratus


Uncharacterized TMEM176 homologue of 326 aas and an apparent 4 TMSs in a 3 + 1 TMS arrangement with a C-terminal annexin domain (see TC# 1.A.31).

UP of Branchiostoma floridae (Florida lancelet) (Amphioxus)