Compositions and methods for modulating connexin hemichannels
Disclosed are compositions and methods for modulating hemichannel function in a cell, tissue or organ. The invention also relates to useful screens for detecting such compounds, particularly those capable of modulating connexin phosphorylation. Further provided are therapeutic methods for preventing or treating conditions impacted by undesired hemichannel function in a mammal such as heart arrhythmia.
1. A method of modulating a hemichannel in a cell, tissue or organ exposed to stress, the method comprising contacting the stressed cell, tissue or organ with a therapeutically effective amount of at least one compound selected from the group consisting of compounds represented as Formula I or II, wherein the contact is sufficient to modulate the hemichannel in the stressed cell, tissue or organ, wherein Formula I is defined as follows:
wherein
R 1 represents H or acetyl (Ac)
R 2 represents a sidechain of one of the amino acids Gly, Tyr, D -Tyr, Phe and D -Phe,
R 3 represents any amino acid sidechain,
R 4 represents a sidechain of one of the amino acids Gly, Tyr, D -Tyr, Phe and D -Phe,
R 5 represents OH or NH 2 ,
and a, S, T, P and Q are integers and independently=0 or 1;
and salts thereof,
and wherein Formula II is defined as follows:
R1-X1-X2-X3-R2
wherein,
X1 is 0, Ala, Gly, β-Ala, Tyr, D -Tyr, Asp,
X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D -Asn- D -Ala, D -Asn, Gly, Ala, D -Ala, β-Ala, Asn or,
X3 is Tyr, D -Tyr, Gly or Phe, and
R1 is H or Ac,
R2 is OH or NH 2 ,
with the proviso that X1 and X2 are not both 0;
and salts thereof.
2. The method of claim 1 , wherein the modulating of the hemichannel is selected from the group comprising closing the hemichannel and opening the hemichannel.
3. The method of claim 2 , wherein the method further comprises phosphorylating a tyrosine residue of connexin 43 (Cx 43) and closing the hemichannel.
4. The method of claim 2 , wherein the method further comprises dephosphorylating a serine residue of connexin 43 (Cx 43) and opening the hemichannel.