8.A.66 The Dystrophin (Dystrophin) Family. Transmembrane protein CD4 and voltage-dependent Ca²⁺ channels (VDCC ; TC# 1.A.1.11.28) within neuromuscular synapses and at the surfaces of muscle cells in normal and dystrophin-mutant worms proved to be regulated by dystrophin (Zhan et al. 2014). Dystrophin is involved in modulating the confinement of VDCC within sarcolemmal membrane nanodomains in response to varying tonus of C. elegans body-wall muscles. In humans, the interaction of filamin A (TC# 8.A.66.1.4), a homologue of dystrophin, with the hyperpolarization-activated cyclic nucleotide-gated K⁺ channel, HCN1 (TC# 1.A.1.5.32), helps to localized HCN1 to specific neuronal areas, and it modulates its channel activity (Gravante et al. 2004).
References:
Dhitavat, J., C. Cobbold, N. Leslie, S. Burge, and A. Hovnanian. (2003). Impaired trafficking of the desmoplakins in cultured Darier''s disease keratinocytes. J Invest Dermatol 121: 1349-1355.
Gravante, B., A. Barbuti, R. Milanesi, I. Zappi, C. Viscomi, and D. DiFrancesco. (2004). Interaction of the pacemaker channel HCN1 with filamin A. J. Biol. Chem. 279: 43847-43853.
Kakinuma, T., H. Ichikawa, Y. Tsukada, T. Nakamura, and B.H. Toh. (2004). Interaction between p230 and MACF1 is associated with transport of a glycosyl phosphatidyl inositol-anchored protein from the Golgi to the cell periphery. Exp Cell Res 298: 388-398.
Leyva-Leyva, M., A. Sandoval, R. Felix, and R. González-Ramírez. (2018). Biochemical and Functional Interplay Between Ion Channels and the Components of the Dystrophin-Associated Glycoprotein Complex. J. Membr. Biol. [Epub: Ahead of Print]
Li, Q., N. Montalbetti, P.Y. Shen, X.Q. Dai, C.I. Cheeseman, E. Karpinski, G. Wu, H.F. Cantiello, and X.Z. Chen. (2005). Alpha-actinin associates with polycystin-2 and regulates its channel activity. Hum Mol Genet 14: 1587-1603.
Lopez-Escamez, J.A., A. Batuecas-Caletrio, and A. Bisdorff. (2018). Towards personalized medicine in Ménière''s disease. F1000Res 7:.
Modarres, H.P. and M.R. Mofradt. (2014). Filamin: a structural and functional biomolecule with important roles in cell biology, signaling and mechanics. Mol. Cell Biomech 11: 39-65.
Nakamura, F., T.P. Stossel, and J.H. Hartwig. (2011). The filamins: organizers of cell structure and function. Cell Adh Migr 5: 160-169.
Smalley, J.L., N. Cho, S.F.J. Ng, C. Choi, A.H.S. Lemons, S. Chaudry, C.E. Bope, J.S. Dengler, C. Zhang, M.N. Rasband, P.A. Davies, and S.J. Moss. (2023). Spectrin-beta 2 facilitates the selective accumulation of GABA receptors at somatodendritic synapses. Commun Biol 6: 11.
Zhan, H., R. Stanciauskas, C. Stigloher, K.K. Dizon, M. Jospin, J.L. Bessereau, and F. Pinaud. (2014). In vivo single-molecule imaging identifies altered dynamics of calcium channels in dystrophin-mutant C. elegans. Nat Commun 5: 4974.
Zhang, Z., H.A. Ledford, S. Park, W. Wang, S. Rafizadeh, H.J. Kim, W. Xu, L. Lu, V.C. Lau, A.A. Knowlton, X.D. Zhang, E.N. Yamoah, and N. Chiamvimonvat. (2016). Distinct subcellular mechanisms for the enhancement of the surface membrane expression of SK2 channel by its interacting proteins, α-actinin2 and filamin A. J. Physiol. [Epub: Ahead of Print]
Examples:
TC#	Name	Organismal Type	Example
8.A.66.1.1	*Dystrophin, Dys-1, of 3,654 aas. Regulates the localization and activity of L-type Ca²⁺ channels and other membrane proteins (Zhan et al.* 2014).**		Dystrophin of Caenorhabditis elegans

8.A.66.1.10	*Spectrin-beta 2 of 2364 aas and 0 or possibly 1 TMS at residue 150. It facilitates the selective accumulation of GABA(A) receptors at somatodendritic synapses (Smalley et al.* 2023).**		Spectrin-β2 of Homo sapiens

8.A.66.1.2	Dystrophin of 3685 aas. Anchors the extracellular matrix to the cytoskeleton via F-actin. It is a component of the dystrophin-associated glycoprotein complex (DGC) which accumulates at the neuromuscular junction and at a variety of synapses in the peripheral and central nervous systems. It has a structural function in stabilizing the sarcolemma and has been implicated in signaling events, synaptic transmission and stabilization of membrane proteins (Zhan et al. 2014). DGC functions in transmembrane signaling by forming supramolecular assemblies that regulate ion channel localization and activity. These interactions are relevant to cell homeostasis, and its alterations may play a role in the etiology and pathogenesis of various disorders affecting muscle and nerve function (Leyva-Leyva et al. 2018).		Dystrophin of Homo sapiens

8.A.66.1.3	α-actinin-2 (ACTN2) of 894 aas. It directly interacts with and regulates the expression of the SK2 channel (TC#1.A.1.16.1) on the cell surface (Zhang et al. 2016). It has a C-terminal calmodulin domain (TC# 8.A.82.1.1), and associates with polycystin-2 (TC# 1.A.5.2.4), regulating its channel activity (Li et al. 2005). .		α-actinin-2 of Homo sapiens

8.A.66.1.4	Filamin A of 2,437 aas with one N-terminal TMS. Also called FLNA, FLN, and FLN1. It helps the SK2 channel (TC# 1.A.1.16.1) insert into the cytoplasmic membrane (Zhang et al. 2016). It shares an N-terminal domain (residues 30 - 260) with other members of the Dystrophin family, but the remainder of the protein is not apparently homologous. The interaction of filamin A, a homologue of dystrophin, with the hyperpolarization-activated cyclic nucleotide-gated, HCN1 K⁺ channel (TC# 1.A.1.5.32), helps to localized HCN1 to specific neuronal areas, and filamin A also modulates channel activity (Gravante et al. 2004).		Filamin A of Homo sapiens

8.A.66.1.5	Filamin-B, FLNB or FLN2, of 2602 aas; 70% identical to Filamin-A (TC# 8.A.66.1.4). Connects cell membrane constituents to the actin cytoskeleton and links actin filaments to membrane glycoproteins. Interactions with several proteins, including the SK2 channel (TC# 1.A.1.16.1) regulate their activites, influencing signal transduction (Modarres and Mofradt 2014).		FLNB of Homo sapiens

8.A.66.1.6	Filamin-C (FLNC; Flln3) of 2725 aas. It is the muscle-specific filamin, which plays a central role in muscle cells, probably by functioning as a large actin-cross-linking protein. May be involved in reorganizing the actin cytoskeleton in response to signaling events, and may also display structural functions at the Z lines in muscle cells. Critical for normal myogenesis and for maintaining the structural integrity of the muscle fibers (Modarres and Mofradt 2014). Over 90 binding partners, including channels, receptors, intracellular signaling molecules, and transcription factors for filamins have been identified (Nakamura et al. 2011). Due to this diversity, mutations in human FLN genes result in a wide range of anomalies with moderate to lethal consequences.		FLNC of Homo sapiens

8.A.66.1.7	Dystrobrevin α of 743 aas and possibly two close TMSs near the N-terminus. May play roles in the formation and stability of synapses as well as in the clustering of nicotinic acetylcholine receptors. It may also play a role in Meniere's Disease (Lopez-Escamez et al. 2018).		Dystrobrevin-alpha of Homo sapiens

8.A.66.1.8	Microtubule-actin cross-linking factor 1, MACF1, isoforms 1/2/3/5 of 7,388 aas and 2 - 4 TMSs. Two TMSs are near the N- and C-termini of the protein, but two additional peaks of hydrophobicity that may be TMSs are found internally. The protein plays a role in delivery of transport vesicles containing GPI-linked proteins from the trans-Golgi network through its interaction with Golgin-245 (p230 or GOLGA4 of 2230 aas) (Kakinuma et al. 2004). Interaction between p230 and MACF1 is associated with transport of a glycosyl phosphatidyl inositol-anchored proteins from the Golgi to the cell periphery (Kakinuma et al. 2004).		MACF1 of Homo sapiens

8.A.66.1.9	Desmoplakin, DSP, of 2,871 aas and 0 - 2 TMSs. It is the major high molecular weight protein of desmosomes, and is involved in the organization of the desmosomal cadherin-plakoglobin complexes into discrete plasma membrane domains and in the anchoring of intermediate filaments to the desmosomes. It is an adhesin that interacts with PKC, RNA and scafold proteins as part of the cytoskeleton (Dhitavat et al. 2003).		DSP of Homo sapiens