What is the current consensus, if any, on the molecular mechanisms by which octanol and carbenoxolone inhibit gap junction communication? (e.g., direct binding, changes in membrane fluidity)
the moelcules interact with the cellular lipid membrane and hinder the opening of the gap junction channels. The same mechanism is evoked to explain how some anesthetic molecule block ion channels
As far as I know, it is still not clear what is an exact mechanism of these blockers. There are some studies that show the effect of alkanols by changes in membrane fluidity, however alkanols can make hydrogen bonds with amino acids because of their OH group. It is shown that alcohols (alkanols) may bind with other proteins in their transmembrane domains. There are some evidence that glycyrrhetinic acid and its derivatives, including carbenoxolone, induce connexins dephosphorylation if treated for long time (more than 30 min). But carbenoxolone inhibition of gap junctions completes within 5-10 min.
There is a large literature on this subject. I would start by reading the review by Andy Harris [Harris, A.L. (2001). Emerging issues of connexin channels: biophysics fills the gap. Q.Rev.Biophys. 34, 325-472.]
He points out that the most convincing data regard the acute reduction in intercellullar conductance following treatment with hepatanol or octanol that likely represents a decrease in channel open probabability.
It is not so clear that these molecules all have the same mechanisms of action
They are all "dirty" with multiple effects on other channels, transporters and diverse targets.
As stated by Dr. Ngezahayo, it is likely that many of these molecules partition into the plasma membrane and affect gross physical properties (like fluidity, stiffness, and local curvature) but htey may also affect the local lipid microenvironment of the connexin channels.
I agree with Dr. Beyer. Although the mechanism of action in not completely understood, heptanol or octanol seem to act through modifications of the physical properties (fluidity, stiffness, etc) of the cholesterol-rich domains of the plasma membrane, resulting in a reduction in the open probability of junctional channels (Takens-Kwak et al 1992; Bastiaanse et al 1993).
On the other side, effects of carbenoxolone and other glycyrrhetinic derivatives are less clear. They are supposed to act through changes in phosphorylation and assembly of connexins (Guo et al 1999).
As suggested by Dr. Beyer, all these drugs are non-specific and have multiple side effects in other ion channels, which may explain some of their effects.
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