TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
*1.A.24.1.1









Connexin 43 (gap junction α-1 protein), CX43 (transports ATP, ADP and AMP better than CX32 does; Goldberg et al., 2002). Hemichannels mediate efflux of glutathione, glutamate and other amino acids as well as ATP (Stridh et al., 2008; Kang et al., 2008). CX43 has a half life of ~3 h due to ubiquitination and lysosomal and proteasomal degradation (Leithe and Rivedal, 2007). Cx43 and Cx46 regulate each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells (Banerjee et al., 2011). A mutant form of Connexin 43 causes Oculodentodigital dysplasia (Gabriel et al., 2011).  Suppressing the function of Cx43 promotes expression of wound healing-associated genes and hibitits scarring (Tarzemany et al. 2015).  Channel conductance and size selectivity are largely determined by pore diameter, whereas charge selectivity results from the amino-terminal domains; transitions between fully open and (multiple) closed states involves global changes in structure of the pore-forming domains (Ek Vitorín et al. 2016). The human Cx43 orthologue is almost identical to the rat protein.  It may mediate resistance against the parkinsonian toxin, 1-methyl-4-phenylpyridine (MPP+) which induces apoptosis in neuroblastoma cells by modulating mitochondrial apoptosis (Kim et al. 2016).  Dopamine neurons may be the target of MPP+ and play a role in Parkinson's disease.

Eukaryota
Metazoa
CX43 of Rattus norvegicus
*1.A.24.1.2









Connexin 32 (gap junction β1-protein), CX32 (transports adenosine better than CX43 does; Goldberg et al., 2002).  The carboxyl tail regulates gap junction assembly (Katoch et al. 2015).  The modeled channel pore-facing regions of TMSs 1 and 2 were highly sensitive to tryptophan substitution while lipid-facing regions of TMSs 3 and 4 were variably tolerant. Residues facing a putative intracellular water pocket (the IC pocket) were also sensitive.  Interactions important for voltage gating occurred mainly in the mid-region of the channel in TMS 1. TMS 1 of Cx43 was scanned revealing similar but not identical sensitivities (Brennan et al. 2015).

Eukaryota
Metazoa
CX32 of Rattus norvegicus
*1.A.24.1.3









Heteromeric connexin (Cx)32/Cx26) (transports cAMP, cGMP and all inositol phosphates with 1-4 esterified phosphate groups (homomeric Cx26(β2) or homomeric Cx32 do not transport the inositol phosphates as well) (Ayad et al., 2006). The GJB2 gene encodes connexin 26, the protein involved in cell-cell attachment in many tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss as well as various skin disease phenotypes (Iossa et al., 2011). TMS1 regulates oligomerization and function (Jara et al., 2012).  The carboxyl tail pg Cx32 regulates gap junction assembly (Katoch et al. 2015).  In Cx46, neutralization of negative charges or addition of positive charge in the Cx26 equivalent region reduced the slow gate voltage dependence. In Cx50 the addition of a glutamate in the same region decreased the voltage dependence and the neutralization of a negative charge increased it. Thus, the charges at the end of TMS1 are part of the slow gate voltage sensor in Cxs. The fact that Cx42, which has no charge in this region, still presents voltage dependent slow gating suggests that charges still unidentified also contribute to the slow gate voltage sensitivity (Pinto et al. 2016).  Syndromic deafness mutations at Asn14 alter the open stability of Cx26 hemichannels (Sanchez et al. 2016). The Leu89Pro substitution in the second TMS of CX32 disrupts the trafficking of the protein, inhibiting the assembly of CX32 gap junctions, which in turn may result in peripheral neuropathy (Da et al. 2016).  Cx26 mutants that promote cell death or exert transdominant effects on other connexins in keratinocytes lead to skin diseases and hearing loss, whereas mutants having reduced channel function without aberrant effects on coexpressed connexins cause only hearing loss (Press et al. 2017).

Eukaryota
Metazoa
Cx26/Cx32 of Homo sapiens
Cx26 (P29033)
Cx32 (P08034)
*1.A.24.1.4









Connexin 35 hemichannels (activated by depolarization; deactivated by hyperpolarization; expressed in retina and brain (Valiunas et al., 2004).
Eukaryota
Metazoa
Connexin 35 of Danio rerio (Zebrafish)
(Q8JFD6)
*1.A.24.1.5









Heteromeric (or homomeric) Connexin46/Connexin50 junction (Cx46/Cx50)  Mutations in CX46 or Cx50 cause cataracts) (Derosa et al., 2007; Wang and Zhu 2012), and mutations in Cx46 can cause breast cancer (Grek et al. 2016). Cx43 and Cx46 regulate each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells (Banerjee et al., 2011).  The N-terminal half of connexin 46 appears to contain the core elements of the pore and voltage gates (Kronengold et al. 2012).  In Cx46, neutralization of negative charges or addition of positive charge in the Cx26 equivalent region reduced the slow gate voltage dependence. In Cx50 the addition of a glutamate in the same region decreased the voltage dependence and the neutralization of a negative charge increased it. Thus, the charges at the end of TMS1 are part of the slow gate voltage sensor in Cxs. The fact that Cx42, which has no charge in this region, still presents voltage dependent slow gating suggests that charges still unidentified also contribute to the slow gate voltage sensitivity (Pinto et al. 2016).  Cx43 is regulated by phosphorylation of ser-373 (Puebla et al. 2016). A connexin50 mutation in the heterozygous state affects the lipid profile and the oxidative stress parameters in a spontaneously hypertensive rat strain (Šeda et al. 2016).

Eukaryota
Metazoa
Cx46/Cx50 of Homo sapiens:
Cx46 (Q9Y6H8)
Cx50 (P48165)
*1.A.24.1.6









Connexin37 (Cx37). The N-terminus contains an α-helix that is required for channel function (Kyle et al., 2009).
Eukaryota
Metazoa
Connexin37 of Homo sapiens (P35212)
*1.A.24.1.7









Connexin 30 complex (connexin30.2/connexin31.3 (CX30.2/CX31.3)). Also called connexinΥ3/GJC3/GJε1; 279 aas, encoded by the GJB6 (13q12) gene (Cascella et al. 2016)). ATP is released from cells that stably expressed CX30.2 in a medium with low calcium, suggesting a hemichannel-based function. Liang et al. (2011) suggested that it shares functional properties with pannexin hemichannels rather than gap junction channels.  Defects cause nonsyndromic hypoacusia (hearing loss) due to partial loss of channel activity (Su et al. 2012; Su et al. 2013;  Cascella et al. 2016).  Cx30, but not Cx43, hemichannels close upon protein kinase C activation, showing that connexin hemichannels display not only isoform-specific permeability profiles but also isoform-specific regulation by PKC (Alstrom et al. 2015). The W77S mutant has a dominant negative effect on the formation and function of the gap junction and is probably responsible for hearing loss (Wong et al. 2017).

Eukaryota
Metazoa
Cx30.2 of Homo sapiens (Q8NFK1)
*1.A.24.1.8









Connexin40 (Cx40; Gap Junction Protein δ4; GJδ4) of 370 aas and 4 TM (Kopanic et al. 2015).

Eukaryota
Metazoa
Cx40 of Homo sapiens
*1.A.24.1.9









Gap junction epsilon-1 protein, Gjf1 of 205 aas and 4 TMSs.  Mutations result in variable small eyes and affect lens development (Puk et al. 2008).

Eukaryota
Metazoa
Gjf1 of Mus musculus
*1.A.24.1.10









 

Connexin31, Cx31 of 270 aas and 4 TMSs.  Also called the gap junction β-3 protein. Mutation Thr202Asn in TMS4 gives rise to erythrokeratodermia (Sugiura et al. 2015).

Eukaryota
Metazoa
Cx31 of Homo sapiens
*1.A.24.1.11









Gap junction α-1 protein, GJα-1, Cx43, shf, sof, of 281 aas and 4 TMSs.  Can function both as a gap junction and a hemichannel and plays critical diverse roles in zebrafish bone growth (Misu et al. 2016).

Eukaryota
Metazoa
Cx43 of Danio rerio (Zebrafish) (Brachydanio rerio)
*1.A.24.1.12









Connexin 29 (Cx29, Gjc3, Gje1) of 269 aas and 4 TMSs.  The Cx29E269D mutant has a dominant negative effect on the formation and function of gap junctions, explaining the role Cx29 in the development of hearing loss (Hong et al. 2010).  Direct axon-to-myelin linkage by abundant KV1 (TC# 1.A.1.2.10 and 12)/Cx29 channel interactions in rodent axons supports the idea of an electrically active role for myelin in increasing both the saltatory conduction velocity and the maximal propagation frequency in mammalian myelinated axons (Rash et al. 2016).

Eukaryota
Metazoa
Cx29 of Mus musculus
*1.A.24.2.1









Connexin 47 gap junction (catalyzes intercellular diffusion of neurobiotin, Lucifer yellow and 4',6-diamidino-2-phenylindole; expressed in brain and spinal cord neurons) (Teubner et al., 2001). Possesses sequences between TMSs 2 and 3 and following TMS 4 that differ from these regions in most other connexins.
Eukaryota
Metazoa
Connexin 47 of Mus musculus
(Q8BQU6)
*1.A.24.2.2









Invertebrate cordate Connexin 47 (White et al., 2004).

Eukaryota
Metazoa
Connexin 47 of Halocynthia pyriformis (Q6U1M0)
*1.A.24.2.3









Inverebrate cordate Connexin (Hervé et al., 2005).

Eukaryota
Metazoa
Connexin of Oikopleura dioica (E4YIP4)
*1.A.24.2.4









Connexin45 (cx45; Gap Junction protein γ1; GJγ1; CxG1) of 396 aas and 4 TMSs (Kopanic et al. 2015).

Eukaryota
Metazoa
Cx45 of Homo sapiens