Gap 19: Specifically block Cx43 hemichannels inhibitor



Gap 19 is a nonapeptide derived from the cytoplasmic loop (CL) of Connexin-43 (Cx43). Cx43 is a predominant cardiac connexin, and forms gap junctions (GJs) that facilitate electrical cell-cell coupling and unapposed/nonjunctional hemichannels that provide a pathway for the exchange of ions and metabolites between cytoplasm and extracellular milieu. Peptides mimicking cytoplasmic loop (CL) sequences have been used in the past as control peptides that do not inhibit GJs. Gap 19 has high affinity to Cx43 hemichannels, and strongly inhibit plasma membrane Cx43 hemichannels.

Biological Activity

Researches have shown that Gap 19 strongly inhibits Cx43 hemichannels (half-maximal effect at 7μM when applied intracellularly) as exemplified by ATP release and dye uptake assays, and has no effect on gap junctional conductance the first 30min and to even slightly stimulate gap junctions upon 24h exposure. Surface plasmon resonance (SPR) experiments also showed that Gap 19 interacts with the Cx43 C-terminus (CT) and hemichannel inhibition was counteracted by a peptide identical to the last AAs of the CT, which indicating that preventing intramolecular interactions of the CT with CL causes the Gap 19 inhibition of hemichannels. Gap 19 has a good membrane permeability because of the high content of lysine, and its cell permeation can be significantly improved by linking it to a TAT cell-internalization sequence . Moreover, Gap 19 inhibited the potentiation of unitary hemichannel currents in acutely isolated ventricular cardiomyocytes if exposed to metabolic inhibition.


Astrocytes expresses the highest amount of connexins (Cxs) in the brain, and this family of membrane proteins is the molecular constituent of gap junction channels and hemichannels that provide pathways for direct cytoplasm-to-cytoplasm and inside and out exchange, respectively. GJ channels are essential for the function of the heart and blood vessels by providing electrical coupling and direct cell–cell transfer of chemical/metabolic signals. Gap 19 is specific not only for hemichannels but also for the Cx43 protein. Moreover, Gap 19 neither blocks Panx1 channels, nor affects Cx40 hemichannels, and Gap 19 might allow in vitro and in vivo work aimed at determining the role of hemichannels in cardiac disease models, as well as in other tissues and organs that display a prominent Cx43 expression.


1. Wang, N., De Vuyst, E., Ponsaerts, R., Boengler, K., Palacios-Prado, N., Wauman, J., ... & Vinken, M. (2013). Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic research in cardiology, 108(1), 309.

2. Sáez, J. C., & Leybaert, L. (2014). Hunting for connexin hemichannels. FEBS letters, 588(8), 1205-1211.

3. Abudara, V., Bechberger, J., Freitas-Andrade, M., De Bock, M., Wang, N., Bultynck, G., ... & Giaume, C. (2014). The connexin43 mimetic peptide Gap19 inhibits hemichannels without altering gap junctional communication in astrocytes. Frontiers in cellular neuroscience, 8, 306.

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