Mimetic Peptides as Blockers of Connexin Channel-Facilitated Intercellular Communication

Figures & data

Table 1 Cx-mimetic peptides: structures and properties

Name	Cx iso form/sequence	Cx domain	Properties	Reference(s)
Gap peptides
Gap 26	43, 32, 26	64-76 EL1	Inhibits CxHc within minutes and gap junctions	(see text)
	VCYDKSFPISHVR		later in a wide range of cells
Gap 27/43	43, 37, 32, 26	201-211 EL2	Inhibits CxHc within minutes and gap junctions	(see text)
(^43Gap 27)	SRPTEKTIFII		later in a wide range of cells
Gap 27/40	40	201-211 EL2	Inhibits Cx40 gap junctions	(Martin et al., 2005)
(^40Gap27)	SRPTEKNVFIV
Gap24	32	100-122 IL	Inhibits Cx32Hc and not gap junctions	(De Vuyst et al., 2006)
	GHGDPLHLEEVKC
L2 peptide	43	119-144 IL	Influences gap junction channel gating	(Seki et al., 2004)
	DGVNVEMHLKQIEIK
	KFKYGIEEHGK
Other peptides
No name	43	180-195 EL2	Inhibits Cx43 gap junctions	(Kwak and Jongsma, 1999)
	SLSAVYTCKRDPCPHE
No name	40	177-192 EL2	Inhibits Cx40 gap junctions	(Kwak and Jongsma, 1999)
	FLDTLHVCRRSPCPHP
No name	32	52-63 EL1	Inhibits Cx32 gap junctions in hepatocytes	(Eugenin et al., 1998)
	ICNTLQPGCNSV
Peptide	43	54-66 EL1	Inhibits gap junctions in dendritic cells	(Mendoza-Naranjo et al., 2007)
1848	CNTQQPCCENVCY

Figure 1 A proposed mechanism of action by which Cx-mimetic peptides inhibit CxHc and gap junctions. Hemichannels in unapposed regions of the cell's plasma membrane open and release ATP. Peptides bind to channel external domains causing closure, thus limiting ATP release. CxHc: peptide complexes move laterally in the plasma membrane, dock and accrete into gap junctions that become closed thus impairing intercellular coupling/communication. Peptides may also diffuse into intercellular spaces, bind to CxHc and gap junctions also inducing their closure. Connexin channel gating may also be regulated indirectly by changes in sub-plasma membrane Ca levels caused by binding of the peptides to CxHc and influencing, for example, Ca entry into cells. Reproduced with permission of the Biochemical Journal.

Martin P EM, Wall C, Griffith T M. Effects of connexin-mimetic peptides on gap junction functionality and connexin expression in cultured vascular cells. Br J Pharmacol 2005; 144: 617–627

 PubMed Web of Science ®Google Scholar

De Vuyst E, Decrock E, Cabooter L, Dubyak G R, Naus C C, Evans W H, Leybaert L. Intracellular calcium changes trigger connexin 32 hemichannel opening. EMBO J 2006; 25: 34–44

 PubMed Web of Science ®Google Scholar

Seki A, Duffy H S, Coombs W, Spray D C, Taffet S M, Delmar M. Modifications in the biophysical properties of connexin43 channels by a peptide of the cytoplasmic loop region. Circ Res 2004; 95: e22–e28

 PubMed Web of Science ®Google Scholar

Kwak B R, Jongsma H J. Selective inhibition of gap junction channel activity by synthetic peptides. J Physiol 1999; 516: 679–685, (Pt 3)

 PubMed Web of Science ®Google Scholar

Eugenin E A, Gonzalez H, Saez C G, Saez J C. Gap-junctional communication coordinates vasopressin-induced glycogenolysis in rat hepatocytes. Am J Physiol 1998; 274: G1109–G1116

 PubMed Web of Science ®Google Scholar

Mendoza-Naranjo A, Saez P J, Johansson C C, Ramirez M, Mandakovic D, Pereda C, Lopez M N, Kiessling R, Saez J C, Salazar-Onfray F. Functional gap junctions facilitate melanoma antigen transfer and cross-presentation between human dendritic cells. J Immunol 2007; 178: 6949–6957

 PubMed Web of Science ®Google Scholar